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The Future of Drug Safety: Promoting and Protecting the

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The Future of Drug Safety: Promoting and Protecting the Health of the Public
THE FUTURE OF
DRUG SAFETY
PROMOTING AND PROTECTING THE HEALTH OF THE PUBLIC
Committee on the Assessment of the US Drug Safety System
Board on Population Health and Public Health Practice
Alina Baciu, Kathleen Stratton, Sheila P. Burke, Editors
Copyright National Academy of Sciences. All rights reserved.

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Library of Congress Cataloging-in-Publication Data
Institute of Medicine (U.S.). Committee on the Assessment of the US Drug Safety System.
The future of drug safety : promoting and protecting the health of the public / Committee on
the Assessment of the US Drug Safety System, Board on Population Health and Public Health
Practice ; Alina Baciu, Kathleen Stratton, Sheila P. Burke, editors.
p. ; cm.
Includes bibliographical references.
ISBN 978-0-309-10304-6 (pbk.)
1. Pharmaceutical policy—United States. 2. United States. Food and Drug Administration. 3.
Drugs—Safety measures—United States. I. Baciu, Alina. II. Stratton, Kathleen R. III. Burke,
Sheila P. IV. Title.
[DNLM: 1. United States. Food and Drug Administration. 2. Drug Approval—United States.
3. United States Government Agencies—United States. QV 771 I5852f 2007]
RA401.A3.I568 2007
362.17′82—dc22
2006039224
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COMMITTEE ON THE ASSESSMENT

OF THE US DRUG SAFETY SYSTEM
SHEILA P. BURKE, M.P.A., R.N. (Chair), Deputy Secretary and Chief
Operating Officer, Smithsonian Institution, Washington, DC
DAVID BLUMENTHAL, M.D., M.P.P., Samuel O. Thier Professor
of Medicine and Health Policy, Harvard Medical School; Director,
Institute for Health Policy, Massachusetts General Hospital/Partners
Health Care System, Boston
SIR ALASDAIR BRECKENRIDGE, C.B.E., Chairman, Medicines and
Healthcare Product Regulatory Agency, London, UK
R. ALTA CHARO, J.D., Warren P. Knowles Professor of Law & Bioethics,
University of Wisconsin-Madison, WI; Visiting Professor of Law,
University of California, Berkeley (2006)
SUSAN EDGMAN-LEVITAN, P.A., Executive Director, John D. Stoeckle
Center for Primary Care Innovation, Massachusetts General Hospital,
Boston
SUSAN S. ELLENBERG, Ph.D., Department of Biostatistics and
Epidemiology, Center for Clinical Epidemiology and Biostatistics,
University of Pennsylvania School of Medicine, Philadelphia
ROBERT D. GIBBONS, Ph.D., Director, Center for Health Statistics,
University of Illinois at Chicago
GEORGE HRIPCSAK, M.D., M.S., Professor of Biomedical Informatics,
Vice Chair, Department of Biomedical Informatics, Columbia University,
New York
DAVID KORN, M.D., Senior Vice President, Division of Biomedical and
Health Sciences Research, Association of American Medical Colleges,
Washington, DC
DAVID MELTZER, M.D., Ph.D., Section of General Internal Medicine,
University of Chicago, IL
WOODROW A. MYERS, Jr., M.D., M.B.A., Former Executive Vice
President and Chief Medical Officer, Wellpoint Inc, CA
MARY K. OLSON, Ph.D., Associate Professor of Economics and Political
Economy, Tulane University, New Orleans, LA
BRUCE M. PSATY, M.D., Ph.D., Professor, Medicine and Epidemiology,
Co-director, Cardiovascular Health Research Unit, University of
Washington, Seattle
CHRISTOPHER H. SCHROEDER, J.D., Charles S. Murphy Professor of
Law, Public Policy Studies Director, Program in Public Law, Duke Law
School, Durham, NC
ANDY STERGACHIS, Ph.D., R.Ph., Professor of Epidemiology and
Adjunct Professor of Pharmacy, Interim Chair, Pathobiology, Northwest
Center for Public Health Practice, School of Public Health and
Community Medicine, University of Washington, Seattle


Board on Population Health and Public Health Practice Board Liaison
GEORGE ISHAM, M.D., M.S., Medical Director and Chief Health

Officer, HealthPartners, Minneapolis, MN
Study Staff
KATHLEEN STRATTON, Ph.D., Study Director

ALINA BACIU, M.P.H., Program Officer
ANDREA PERNACK ANASON, M.P.H., Program Officer (through
September 2005)
AMY GROSSMAN, M.P.H., Senior Health Policy Associate
RUTH KANTHULA, M.P.H., Senior Project Assistant (through June 2006)
NORMAN GROSSBLATT, ELS (D), Senior Editor
RENIE SCHAPIRO, M.P.H., Consultant
ROSE MARIE MARTINEZ, Sc.D., Director, Board on Population Health
and Public Health Practice
vi

Reviewers
This report has been reviewed in draft form by individuals chosen for
their diverse perspectives and technical expertise, in accordance with pro-
cedures approved by the NRC’s Report Review Committee. The purpose
of this independent review is to provide candid and critical comments that
will assist the institution in making its published report as sound as possible
and to ensure that the report meets institutional standards for objectivity,
evidence, and responsiveness to the study charge. The review comments
and draft manuscript remain confidential to protect the integrity of the
deliberative process. We wish to thank the following individuals for their
review of this report:
J. Lyle Bootman, College of Pharmacy–Pulido Center, The University

of Arizona
John E. Calfee, American Enterprise Institute, Washington, DC
Dan Carpenter, Center for Government and International Studies,
Harvard University
Ralph Edwards, The Uppsala Monitoring Centre, World Health
Organization
David W. Feigal, NDA Partners, LLP and Arizona Biodesign Center
Garrett Fitzgerald, University of Pennsylvania School of Medicine
Henry G. Grabowski, Department of Economics, Program in
Pharmaceuticals and Health Economics, Duke University
Sean Hennessy, University of Pennsylvania School of Medicine
Peter Barton Hutt, Covington & Burling
vii

viii REVIEWERS
Anne Khademian, Center for Public Administration and Policy,

Virginia Tech
Debra R. Lappin, B&D Sagamore, Washington, DC
Arthur Aaron Levin, Center for Medical Consumers, New York
Steven M. Paul, Lilly Research Laboratories, Eli Lilly and Company
Richard Platt, Department of Ambulatory Care and Prevention,
Harvard Medical School
Wayne A. Ray, Department of Preventive Medicine, Vanderbilt
University School of Medicine
Joshua M. Sharfstein, Health Department, City of Baltimore
Panos Tsintis, Unit for the Post-Authorisation Evaluation of Medicines
for Human Use, European Medicines Agency, London
Eleanor M. Vogt, School of Pharmacy, University of California, San
Francisco
Alastair J.J. Wood, Vanderbilt University Medical School
Although the reviewers listed above have provided many constructive

comments and suggestions, they were not asked to endorse the conclusions
or recommendations nor did they see the final draft of the report before its
release. The review of this report was overseen by Neal A. Vanselow, Tulane
University, Professor Emeritus and Joseph P. Newhouse, Harvard University.
Appointed by the National Research Council and Institute of Medicine,
they were responsible for making certain that an independent examination
of this report was carried out in accordance with institutional procedures
and that all review comments were carefully considered. Responsibility for
the final content of this report rests entirely with the authoring committee
and the institution.

Preface
The year 2006 marks the 100th anniversary of the signing of the Pure
Food and Drug Act. During that century, drug regulation at the Food and
Drug Administration (FDA) has evolved enormously, both in terms of statu-
tory reforms (with major legislation in 1938, 1962, 1992, 1997, and 2002)
and due to internal restructuring and growth in staff. Past changes have
frequently been responses to problems in the functioning of the drug regula-
tory process. Although the agency has gained great respect and importance
as one of the world’s premier regulatory bodies, recent drug safety events
have called into question FDA’s regulatory decision-making and oversight
processes, and caused the public to question its ability to accomplish a bal-
anced evaluation of the safety and efficacy of the drugs it reviews and after
their approval, of their performance under real-life conditions. In light of
these developments, the Institute of Medicine (IOM) was asked by FDA to
examine in detail the system of drug safety in this country. Our committee
has, in the course of the last 15 months, undertaken this assessment.
The result of our review is a series of recommendations that we believe
will improve the drug safety system by strengthening clinical and epide-
miological research, and the scientific basis of regulatory action. Although
mindful of recent actions by FDA to improve its postmarketing decision-
making process, the committee believes a more comprehensive response is
required that acknowledges the need for vigilance throughout the lifecycle
of a drug. Underlying our 25 recommendations is the fundamental view
that the interests of the public are best served when safety and efficacy
are considered together. However, factors including, but not limited to,
the current organizational culture of the Center for Drug Evaluation and
ix

PREFACE
Research (CDER), combined with severe resource constraints and a prob-

lematic funding mechanism have impeded the development of a system
that optimally integrates the safety and efficacy assessments along a drug’s
lifecycle, particularly with regard to safety issues arising postmarketing.
Further complicating this problem is the lack of a clearly established and
consistently applied systematic process of making risk-benefit assessments,
and an adequate base of human and technological resources required to
meet the center’s critical responsibilities.
The committee believes that CDER staff are a dedicated and talented
group of public servants who currently lack the organization and resources
to address all of the challenges before them and perform the crucial role
of advancing and protecting public health in an increasingly complex
environment.
We believe that Congress needs to ensure that CDER is given the au-
thority and assets (human, financial, technological) it requires. The center’s
leaders have to be prepared to address the underlying cultural problems that
divide and impair the optimal functioning of center staff, and to effectively
use existing and new authorities and resources to achieve the center’s public
health and regulatory mission. The committee’s recommendations pertain-
ing to these issues must be viewed as a coherent package of solutions or
strategies rather than a menu of choices.
I would like to thank my colleagues on the committee for their ex-
traordinary efforts. They have committed countless hours over the last
15 months in meetings, weekly conference calls, and a continuous stream
of emails. They have passionately argued their positions, but also accom-
modated their colleagues and sought responsible consensus. I thank them
for all they have done. I would also like to acknowledge the contributions
of the IOM staff team—Kathleen Stratton, Alina Baciu, Amy Grossman,
Ruth Kanthula, Andrea Pernack Anason, and consultant Renie Schapiro.
Their dedication, guidance, and experience were of inestimable value to us
in examining the highly complex process of drug evaluation and regulation.
We could not have produced this report without them. The committee is
grateful to everyone who spoke at our public meetings and who sent mate-
rial for consideration. I also wish to thank the current and former staff at
FDA and particularly CDER who spoke frankly with the committee and
provided much needed insight into the workings of this agency.
Sheila P. Burke, Chair

Contents
SUMMARY 1
1 INTRODUCTION 15
Changes in the Broad Context of Drug Regulation, 19
Defining and Meeting the Charge, 21
2 NATURAL HISTORY OF A DRUG 31

Economic Impact of Drugs, 32
The Investigational New Drug, 33
Investigational New Drug Submission and Review, 33
New Drug Application, 39
Postmarket Period, 51
3 A CULTURE OF SAFETY 65
Organizational Challenges, 65
The External Environment, 68
Structural Factors, Policies, and Procedures, 75
Proposed Solutions to CDER’s Organizational Dysfunction, 90
4 THE SCIENCE OF SAFETY 105

Generating the Science, 106
Understanding Risk and Benefit for Approval Decisions, 106
Reducing Uncertainty About Risk and Benefit After Approval, 107
Risk Minimization Action Plans, 119
Risk-Benefit Analyses Throughout the Lifecycle, 121
xi

xii CONTENTS
Credibility of the Science, 126

Expertise in the Center for Drug Evaluaiton and Research, 127
Advisory Committees, 131
Transparency, 142
5 REGULATORY AUTHORITIES FOR DRUG SAFETY 151

History of FDA Drug Regulation, 152
An Aging and Inadequate Statutory Framework, 153
FDA Authority Preapproval, 154
FDA Authority After Approval, 155
Rationale for Strengthening Drug Regulation, 164
Strengthening FDA’s Regulatory Authorities, 167
6 COMMUNICATING ABOUT SAFETY 177

Roles and Needs of Providers and Patients, 178
How Industry Communicates to the Public and Patients, 184
FDA’s Challenges in Communicating to the Public and
Patients, 184
7 RESOURCES FOR THE DRUG SAFETY SYSTEM 193
APPENDIXES
A Moving Target: Changes at FDA During the Course of the Study 205
B Acronyms 217
C PDUFA Performance Goals—All Years 221
D Committee on the Assessment of the US Drug Safety System
Meeting Agendas 255
E Summary, Preventing Medication Errors: Quality Chasm Series,
Institute of Medicine 267
F Committee Biographies 309
INDEX 319

THE FUTURE OF
DRUG SAFETY
PROMOTING AND PROTECTING THE HEALTH OF THE PUBLIC


Summary
Every day the Food and Drug Administration (FDA) works to balance
expeditious access to drugs with concerns for safety, consonant with its
mission to protect and advance the public health. The task is all the more
complex given the vast diversity of patients and how they respond to drugs,
the conditions being treated, and the range of pharmaceutical products and
supplements patients use. Reviewers in the Center for Drug Evaluation and
Research (CDER) at the FDA must weigh the information available about
a drug’s risk and benefit, make decisions in the context of scientific uncer-
tainty, and integrate emerging information bearing on a drug’s risk-benefit
profile throughout the lifecycle of a drug, from drug discovery to the end
of its useful life. These processes may have life-or-death consequences for
individual patients, and for drugs that are widely used, they may also affect
entire segments of the population. The distinction between individual and
population is important because it reflects complex determinations that
FDA must make when a drug that is life-saving for a specific patient may
pose substantial risk when viewed from a population health perspective. In
a physician’s office, the patient and the provider make decisions about the
risk and benefits of a given drug for that patient, whereas FDA has to assess
risks and benefits with a view toward their effects on the population. The
agency has made great efforts to balance the need for expeditious approvals
with great attention to safety, as reflected in its mission—to protect and
advance the health of the public.
In the first years of the 21st century, the issue of prescription drug safety
came to the attention of the public with renewed intensity. Drug withdraw-
als, apparent delays in warning the public about important drug risks, a

THE FUTURE OF DRUG SAFETY
perceived rush to approve drugs without sufficient attention to safety, and

press coverage of internal problems in CDER may have contributed to a
deterioration of public confidence in FDA. Academics, consumer organiza-
tions, professional societies, and legislators debated the possible causes
and solutions of what was seen by many as a major problem (Consumers
Union, 2005; Grassley, 2005; NCL, 2005; US PIRG, 2006). FDA and the
Department of Health and Human Services (DHHS) announced a series
of steps to address drug safety, including asking the Institute of Medicine
(IOM) to convene a committee to assess the US drug safety system and to
make recommendations to improve risk assessment, surveillance, and the
safe use of drugs.
In its report, the committee considered the drug safety system as the sum
of all activities conducted by FDA and other stakeholders to monitor, evalu-
ate, improve, and ensure drug safety. (See the committee’s Statement of Task
in Box S-1.) Although much of the committee’s work was focused on drug
review, safety surveillance, and related activities of CDER, the committee
also reviewed some key aspects of the roles and considered the potential con-
tributions of the pharmaceutical industry, the academic research enterprise,
Congress, the health care delivery system, patients, and the public.
Some observers believe that drug withdrawals (which are only one
potential indicator of drug safety) represent de facto failures of the drug
regulatory system, or that newly identified unusual and serious adverse
events indicate that someone made a mistake in approving the drug. This
is not so. FDA approval does not represent a lifetime guarantee of safety
and efficacy, and what is newest is not always the best. For several related
reasons, even the best drug safety system would not prevent adverse reac-
tions to pharmaceuticals on the market. It is impossible to know everything
about a drug at the point of approval because drugs’ mechanisms of action
are complex, and because the clinical testing that happens before approval
is generally conducted in controlled settings in defined, carefully selected
populations that may not fully represent the wide range of patients who
will use the drug after approval, some chronically, and in combination with
other drugs. Thus, the understanding of a drug’s risk-benefit profile neces-
sarily evolves over the drug’s lifecycle. CDER staff who review regulatory
submissions, such as new drug applications, must strike a delicate balance
in judging the drug’s risks and benefits, and whether the need for more study
to increase certainty before approval warrants delaying the release of the
drug into the marketplace and into the hands of health care providers and
their patients.
Legitimate questions have arisen about CDER’s handling of drug safety.
Are safety signals recognized and addressed in a timely fashion? Is the pub-
lic informed about safety problems in a clear and timely manner? Do the
interactions of pre- and postmarketing center staff facilitate effective action

SUMMARY
BOX S-1
The Statement of Task
In response to growing public concern with health risks posed by
approved drugs, the FDA has requested that the Institute of Medicine
(IOM) convene an ad hoc committee of experts to conduct an inde-
pendent assessment of the current system for evaluating and ensuring
drug safety postmarketing and make recommendations to improve risk
assessment, surveillance, and the safe use of drugs. As part of its work,
the IOM committee will:
• examine the FDA’s current role and the role of other actors (e.g.,
health professionals, hospitals, patients, other public agencies)
in ensuring drug safety as part of the US health care delivery
system;
• examine the current efforts for the ongoing safety evaluation of
marketed drug products at the FDA and by the pharmaceutical
industry, the medical community, and public health authorities;
• evaluate the analytical and methodological tools employed by
FDA to identify and manage drug safety problems and make
recommendations for enhancement;
• evaluate FDA’s internal organizational structure and operations
around drug safety (including continuing postmarket assessment
of risk vs. benefit);
• consider FDA’s legal authorities for identifying and responding to
drug safety issues and current resources (financial and human)
dedicated to postmarketing safety activities;
• identify strengths, weaknesses, and limitations of the current
system; and
• make recommendations in the areas of organization, legislation,
regulation, and resources to improve risk assessment, surveil-
lance, and the safe use of drugs.
on drug safety? Does the center have the mix of expertise, technology, scien-
tific capacity, authority, and resources to achieve its share of FDA’s mission,
to protect and advance the health of the public? Do the political, social,
and economic aspects of the external environment and the expectations of
other stakeholders affect the agency’s functioning? To answer some of these
questions, the committee reviewed aspects of the drug safety system that it
believes can be transformed to improve the monitoring and evaluation of
drug safety signals and restore public confidence in the system, including:

• The organizational culture of CDER and its determinants, and how

organizational culture may affect the center’s performance in assess-
ing and acting on the evolving understanding of risk and benefit over
the drug lifecycle;
• Key factors of regulatory science and processes (methods, data
resources, expert advice, independence) necessary to enhance drug
safety;
• The regulatory authorities necessary to provide for drug safety;
• The communication structure needed to support an effective drug
safety system; and
• The financial resources required to enable CDER to meet its respon-
sibilities in supporting the FDA mission.
In its information gathering, the committee became aware of multiple

proposals to strengthen the drug safety system that have been made in
the past and have addressed many of the areas outlined. In its work, the
committee has attempted to develop a coherent and integrative approach
to transforming drug safety programs that encompasses the categories de-
scribed above. The committee made several overarching findings. First, there
is a perception of crisis that has compromised the credibility of FDA and
of the pharmaceutical industry (Harris Interactive, 2005; Pricewaterhouse
Coopers’ Health Research Institute, 2005). Second, the committee learned
that most stakeholders—the agency, the industry, consumer organizations,
Congress, professional societies, health care entities—appear to agree on the
need for certain improvements in the system. Third, the committee found
that the drug safety system is impaired by the following factors: serious
resource constraints that weaken the quality and quantity of the science
that is brought to bear on drug safety; an organizational culture in CDER
that is not optimally functional; and unclear and insufficient regulatory
authorities particularly with respect to enforcement. Fourth, the committee
found that FDA, contrary to its public health mission, and the pharma-
ceutical industry, contrary to its responsibility to the users of its products
(and its shareholders), do not consistently demonstrate accountability and
transparency to the public by communicating safety concerns in a timely
and effective fashion.
The committee’s vision of a transformed drug safety system has at its
core a lifecycle approach to drug risk and benefit—not a new concept, but
one that has been implemented, at best, in a limited and fragmented manner.
For FDA, attention to risk and benefit over a drug’s lifecycle would require
continuous availability of new data and ongoing, active reassessment of risk
and benefit to drive regulatory action (responsive to the accumulating in-
formation about a given drug), and regulatory authority that is strong both
before and after approval. For the industry, attention to risk and benefit over

SUMMARY
the lifecycle will require increased transparency toward FDA in the process
of elucidating and communicating emerging information about a drug,
and acceptance of changes intended to strengthen drug safety. Importantly,
FDA’s credibility is intertwined with that of the industry, and a more credible
drug safety system is in everyone’s best interest. For the health care delivery
system, a lifecycle approach to risk and benefit implies the need to heed
and follow FDA communication about drug safety matters and to exercise
appropriate caution in drug-related decision making (from formularies to
prescribing) in recognition of the limited information available at the time
of drug approval. Also, the health care delivery system would benefit from
consistently basing prescribing decisions on the science, and exercising cau-
tion in regard to the industry’s influence on the practice of medicine. Health
care organizations and professional societies could contribute to prescribers’
understanding of the evolving science behind the assessment of drug risk and
benefit. The academic research enterprise could enhance its contributions of
data to the assessment of risk and benefit at all points in a drug’s lifecycle,
continue its crucial advisory relationship with FDA, and uphold the value
of complete transparency in recognition of real and perceived conflicts as-
sociated with financial involvement with the industry. Other government
agencies could contribute to the lifecycle approach to drug risk and benefit
by collaborating with FDA and the private sector to ensure that data streams
from publicly funded health care settings contribute to an improved drug
safety system. The public and patients could do their part by communicat-
ing with their health care providers about the pharmaceutical products they
are using, learning about and discussing with their providers drug risks and
benefits in the context of their health needs and characteristics, informing
their providers about side effects they experience, and calling for more use-
ful and timelier information about drug benefits and risks associated with
new drugs. The public and other stakeholders could also urge Congress to
ensure and sustain adequate funding for FDA.
RECOMMENDATIONS
Organizational Culture
Instability in the Office of the Commissioner has been a serious problem

for FDA and CDER in particular. A large, complex, science-based regulatory
agency cannot perform optimally in the absence of stable, capable leader-
ship, and clear, consistent direction.
3.1: The committee recommends that the FD&C Act be amended

to require that the FDA Commissioner currently appointed by the
President with the advice and consent of the Senate also be ap-

pointed for a 6-year term of office. The Commissioner should be

an individual with appropriate expertise to head a science-based
agency, demonstrated capacity to lead and inspire, and a proven
commitment to public health, scientific integrity, transparency, and
communication. The President may remove the Commissioner from
office only for reasons of inefficiency, neglect of duty, or malfea-
sance in office.
A mechanism is needed to allow the agency and CDER leadership to

benefit from the advice and support of individuals experienced in changing
organizational culture and leading large and complex organizations.
3.2: The committee recommends that an external Management

Advisory Board be appointed by the Secretary of HHS to advise
the FDA commissioner in shepherding CDER (and the agency as
a whole) to implement and sustain the changes necessary to trans-
form the center’s culture—by improving morale and retention of
professional staff, strengthening transparency, restoring credibility,
and creating a culture of safety based upon a lifecycle approach to
risk-benefit.
3.3: The committee recommends the Secretary of HHS direct the

FDA commissioner and Director of CDER, with the assistance of
the Management Advisory Board, to develop a comprehensive
strategy for sustained cultural change that positions the agency to
fulfill its mission, including protecting the health of the public.
The Office of Drug Safety, now the Office of Surveillance and Epidemi-
ology (OSE), has not had a formal role in drug regulation—neither formal
opportunities to learn from and participate in relevant aspects of the review
process nor the authority to take action regarding postmarketing safety.
3.4: The committee recommends that CDER appoint an OSE staff

member to each New Drug Application review team and assign
joint authority to OND and OSE for postapproval regulatory ac-
tions related to safety.
The Prescription Drug User Fee Act (PDUFA) mechanism that accounts
for over half of CDER’s funding and the reporting requirements associated
with the user-fee program are excessively oriented toward supporting speed
of approval and insufficiently attentive to safety.

SUMMARY
3.5: To restore appropriate balance between the FDA’s dual goals

of speeding access to innovative drugs and ensuring drug safety over
the product’s lifecycle, the committee recommends that Congress
should introduce specific safety-related performance goals in the
Prescription Drug User Fee Act IV in 2007. (See Chapter 3 for
suggested goals.)
Science and Expertise
FDA’s Adverse Event Reporting System (AERS) is outdated and inef-

ficient, and although CDER has begun a technological overhaul of the
system, more work is needed to improve its usefulness in postmarketing
surveillance.
4.1: The committee recommends that in order to improve the gen-

eration of new safety signals and hypotheses, CDER (a) conduct a
systematic, scientific review of the AERS system, (b) identify and
implement changes in key factors that could lead to a more efficient
system, and (c) systematically implement statistical-surveillance
methods on a regular and routine basis for the automated genera-
tion of new safety signals.
In addition, CDER’s ability to test drug safety hypotheses is limited.
4.2: The committee recommends that in order to facilitate the for-

mulation and testing of drug safety hypotheses, CDER (a) increase
their intramural and extramural programs that access and study
data from large automated healthcare databases and (b) include in
these programs studies on drug utilization patterns and background
incidence rates for adverse events of interest, and (c) develop and
implement active surveillance of specific drugs and diseases as
needed in a variety of settings.
The report makes several recommendations (4.3, 4.5, 4.8, and 5.4 be-
low) intended to help CDER develop a more structured way to determine
the level of postmarketing scrutiny and data requirements, in other words,
to match the evaluation of drugs with the way that they will be used in the
population. Short-term preapproval trials do not provide adequate informa-
tion about the balance of risks and benefits of drugs that are used by many
people for many years.
Various public- and private-sector organizations possess increasingly
high-quality data resources and scientific capacity, and a concerted effort is

needed to ensure that those resources are used efficiently and effectively in
the service of drug safety.
4.3: The committee recommends that the Secretary of HHS, work-

ing with the Secretaries of Veterans Affairs and Defense, develop a
public-private partnership with drug sponsors, public and private
insurers, for-profit and not-for-profit health care provider organi-
zations, consumer groups, and large pharmaceutical companies to
prioritize, plan, and organize funding for confirmatory drug safety
and efficacy studies of public health importance. Congress should
capitalize the public share of this partnership.
4.4: The committee recommends that CDER assure the perfor-

mance of timely and scientifically-valid evaluations (whether done
internally or by industry sponsors) of Risk Minimization Action
Plans (RiskMAPs).
The assessment of risks and benefits is an activity that does not end
at approval, and risk and benefit cannot be considered in isolation of one
another.
4.5: The committee recommends that CDER develop and con-

tinually improve a systematic approach to risk-benefit analysis
for use throughout the FDA in the preapproval and postapproval
settings.
The committee has made several recommendations to expand the data

on drug risks and benefits to improve those decisions. However, in order to
plan and use those data, appropriate expertise must be brought to bear. This
expertise comes from the CDER staff as well as their advisory committees
and other non-governmental experts. The committee believes there is a need
to expand this expertise to take on the new responsibilities laid out in recom-
mendations made in this report. CDER will need more expert staff, deeper
expertise in the staff it already has, and different kinds of expertise.
With this expanded expertise and resources CDER can be a more effec-
tive steward of postmarketing safety and a more credible scientific partner
with industry and academia by actively participating in defining important
research questions and designing appropriate studies.
4.6: The committee recommends that CDER build internal epide-

miologic and informatics capacity in order to improve the postmar-
ket assessment of drugs.

SUMMARY
Increasing the scientific sophistication of the CDER staff should not

happen in isolation. Since the goal is to support good science-based regu-
latory decision making, a corollary goal is to support the research infra-
structure of the agency. Expanded research opportunities should be linked
explicitly to FDA’s regulatory mission.
4.7: The committee recommends that the Commissioner of FDA

demonstrate commitment to building the Agency’s scientific re-
search capacity by:
a. Appointing a Chief Scientist in the office of the Commissioner

with responsibility for overseeing, coordinating, and ensuring
the quality and regulatory focus of the agency’s intramural
research programs.
b. Designating the FDA’s Science Board as the extramural advi-
sory committee to the Chief Scientist.
c. Including research capacity in the Agency’s mission statement.
d. Applying resources to support intramural research approved by
the Chief Scientist.
e. Ensuring that adequate funding to support the intramural
research program is requested in the Agency’s annual budget
request to Congress.
The fast pace of review does not allow CDER reviewers to solicit con-
sistently needed input from the appropriate FDA advisory committee(s) on
issues such as postmarketing safety and the need for additional studies.
4.8: The committee recommends that FDA have its advisory com-
mittees review all NMEs either prior to approval or soon after ap-
proval to advise in the process of ensuring drug safety and efficacy
or managing drug risks.
4.9: The committee recommends that all FDA drug product ad-
visory committees, and any other peer-review effort such as men-
tioned above for CDER-reviewed product safety, include a pharma-
coepidemiologist or an individual with comparable public health
expertise in studying the safety of medical products.
FDA’s credibility is its most crucial asset and recent concerns about the
independence of advisory committee members (who advise CDER in its
regulatory decision making), along with broader concerns about scientific
independence in the biomedical research establishment, have cast a shadow
on the trustworthiness of the scientific advice received by the agency.

10 THE FUTURE OF DRUG SAFETY
4.10: The committee recommends FDA establish a requirement

that a substantial majority of the members of each advisory com-
mittee be free of significant financial involvement with companies
whose interests may be affected by the committee’s deliberations.
The committee believes strongly in the importance of increasing the

availability of information about risks and benefits, whether specific study
results or CDER staff analyses of concerns, to the public and to researchers.
The National Library of Medicine hosts a Web site for registration of clinical
trials, but with few exceptions, this is voluntary. In 2002, pharmaceutical
companies that are members of the Pharmaceutical Research and Manu-
facturers of America (PhRMA) committed to voluntary disclosure of the
results of hypothesis-testing clinical trials for marketed and investigational
drugs and in 2004 PhRMA launched a Web site (ClinicalStudyResults.org)
for this purpose. A review of the site shows great variability in the ease of
accessibility and completeness of the information.
4.11: To ensure that trial registration is mandatory, systematic,

standardized, and complete, and that the registration site is able
to accommodate the reporting of trial results, the committee rec-
ommends that Congress require industry sponsors to register in
a timely manner at clinicaltrials.gov, at a minimum, all Phase 2
through 4 clinical trials, wherever they may have been conducted,
if data from the trials are intended to be submitted to the FDA as
part of an NDA, sNDA, or to fulfill a postmarket commitment.
The committee further recommends that this requirement include
the posting of a structured field summary of the efficacy and safety
results of the studies.
4.12: The committee recommends that FDA post all NDA review
packages on the agency’s Web site.
4:13: The committee recommends that the CDER review teams

regularly and systematically analyze all postmarket study results
and make public their assessment of the significance of the results
with regard to the integration of risk and benefit information.
Regulation
FDA lacks the clear, unambiguous authority needed to enforce sponsor

compliance with regulatory requirements and instead relies on the prospect
of productive negotiations with industry. Although the agency historically
has made effective use of its “bully pulpit” to compel sponsor compliance,

SUMMARY 11
this process leaves potentially critical regulatory action vulnerable to a

subjective and highly variable process of exercising individual or agency
influence, and to the vicissitudes of changing politics and attitudes toward
regulation. That is why FDA’s authorities must be clarified and strengthened
to empower the agency to take rapid and decisive actions when necessary
and appropriate.
5.1: The committee recommends that Congress ensure that the

Food and Drug Administration has the ability to require such
postmarketing risk assessment and risk management programs as
are needed to monitor and ensure safe use of drug products. These
conditions may be imposed both before and after approval of a
new drug, new indication, or new dosage, as well as after identifi-
cation of new contraindications or patterns of adverse events. The
limitations imposed should match the specific safety concerns and
benefits presented by the drug product. The risk assessment and
risk management program may include:
a. Distribution conditioned on compliance with agency-initiated

changes in drug labels.
b. Distribution conditioned on specific warnings to be incor-
porated into all promotional materials (including broadcast
direct-to-consumer [DTC] advertising).
c. Distribution conditioned on a moratorium on DTC advertising.
d. Distribution restricted to certain facilities, pharmacists, or
physicians with special training or experience.
e. Distribution conditioned on the performance of specified medi-
cal procedures.
f. Distribution conditioned on the performance of specified ad-
ditional clinical trials or other studies.
g. Distribution conditioned on the maintenance of an active ad-
verse event surveillance system.
5.2: The committee recommends that Congress provide oversight

and enact any needed legislation to ensure compliance by both the
Food and Drug Administration and drug sponsors with the provi-
sions listed above. FDA needs increased enforcement authority and
better enforcement tools directed at drug sponsors, which should
include fines, injunctions, and withdrawal of drug approval.
The agency’s timely performance of the required postmarketing safety

reviews could be listed as one of the goals associated with PDUFA and re-
ported on in the goals letter to Congress (see Chapter 3).

5.3: The committee recommends that Congress amend the Food,

Drug and Cosmetic Act to require that product labels carry a special
symbol such as the black triangle used in the UK or an equivalent
symbol for new drugs, new combinations of active substances, and
new systems of delivery of existing drugs. The Food and Drug Ad-
ministration should restrict direct-to-consumer advertising during
the period of time the special symbol is in effect.
The symbol should remain on the drug label and related materials for
2 years unless FDA chooses to shorten or extend the period on a case-by-
case basis.
5.4: The committee recommends that FDA evaluate all new data
on new molecular entities no later than 5 years after approval.
Sponsors will submit a report of accumulated data relevant to
drug safety and efficacy, including any additional data published
in a peer-reviewed journal, and will report on the status of any
applicable conditions imposed on the distribution of the drug called
for at or after the time of approval.
Communication
The public would benefit from more information about how drugs are
studied before FDA approval, how drugs’ risks and benefits are assessed,
and what FDA review entails. Patients also need timely information about
emerging safety concerns and about a drug’s effectiveness. Such information
would help patients make better decisions in collaboration with their health
care providers. FDA does not have an adequate mechanism for seeking and
receiving specific scientific and patient/consumer advice on communication
matters.
6.1: The committee recommends that Congress enact legislation

establishing a new FDA advisory committee on communication
with patients and consumers. The committee would be composed
of members who represent consumer and patient perspectives and
organizations. The advisory committee would advise CDER and
other centers on communication issues related to efficacy, safety,
and use during the lifecycle of drugs and other medical products,
and it would support the centers in their mission to “help the public
get the accurate, science-based information they need to use medi-
cines and foods to improve their health.”

SUMMARY 13
6.2: The committee recommends that the new Office of Drug

Safety Policy and Communication should develop a cohesive risk
communication plan that includes, at a minimum, a review of all
center risk communication activities, evaluation and revision of
communication tools for clarity and consistency, and priority-
setting to ensure efficient use of resources.
Resources
The suite of recommendations put forward in this report—to improve

the culture in CDER, attract and retain highly qualified staff, improve tech-
nological capacity, obtain and benefit from access to data and innovative
scientific partnerships, and so on—are all dependent on adequate resources.
An agency whose crucial mission is to protect and advance the public’s
health should not have to go begging for resources to do its job. Also, the
effect on CDER’s work of CDER’s overdependence on PDUFA funding
with the strings that are attached hurts FDA’s credibility and may affect the
agency’s effectiveness.
7.1: To support improvements in drug safety and efficacy activi-

ties over a product’s lifecycle, the committee recommends that the
Administration should request and Congress should approve sub-
stantially increased resources in both funds and personnel for the
Food and Drug Administration.
The committee favors appropriations from general revenues, rather

than user fees, to support the full spectrum of new drug safety responsi-
bilities proposed in this report. This preference is based on the expectation
that CDER will continue to review and approve drugs in a timely manner
and that increasing attention to drug safety will not occur at the expense
of efficacy reviews but rather it will complement efficacy review for a life-
cycle approach to drugs. Congressional appropriations from general tax
revenues are a mechanism by which the public can directly, fairly, and ef-
fectively invest in the FDA’s postmarket drug safety activities. However, if
appropriations are not sufficient to fund these activities and user fees are
required, Congress should greatly reduce current restrictions on how CDER
uses PDUFA funds.
The year 2006 marks a major milestone in FDA’s history, public inter-
est in drug safety matters has reached a high point, negotiations in advance
of the September 2007 sunset of PDUFA have begun, Medicare part D has
enrolled millions of senior citizens in a system that has the potential to yield
useful data about experience with drugs, and congressional attention to drug
safety issues has become intense. Now is the time to renew and transform

CDER’s culture, its authorities, its scientific capacity, and its ability to com-
municate with health care providers and the public. The committee believes
that the recommendations contained in this report, implemented together
and with adequate resources, will enable the center (and the agency) to
function more effectively in the present and to position itself for an even
more challenging future in advancing and protecting the health of patients
and the public.
REFERENCES
Consumers Union. 2005. NEWS—IOM Panel Urged to Immediately Recommend that Con-
gress Toughen Drug Safety Laws to Save Lives: Consumers Union Testifies Today That
Obvious Safety Problems Need Action Now. [Online]. Available: http://www.pharmalive.
com/news/print.cfm?articleid=247043 [accessed June 9, 2005].
Grassley C. 2005. S.930: A bill to amend the Federal Food, Drug, and Cosmetic Act with
respect to drug safety, and for other purposes. 109th Congress.
Harris Interactive. 2005. The Public Has Doubts About the Pharmaceutical Industry’s Will-
ingness to Publish Safety Information About Their Drugs in a Timely Manner. [Online].
Available: http://www.harrisinteractive.com/news/printerfriend/index.asp?NewsID=882
[accessed March 10, 2006].
NCL (National Consumers League). 2005. Comments of the National Consumers League to
DKT. No. 2005N-0394, Communication of Drug Safety Information. [Online]. Avail-
able: http://www.nclnet.org/advocacy/health/letter_drugsafety_01062006.htm [accessed
September 16, 2006].
PricewaterhouseCoopers’ Health Research Institute. 2005. Recapturing the Vision: Integrity
Driven Performance in the Pharmaceutical Industry. [Online]. Available: http://www.
pwc.com/extweb/pwcpublications.nsf/docid/EE74BACB6DE454768525702A00630CFF
[accessed February 20, 2006].
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Introduction
“. . . [A]lmost every morning’s newspaper and each evening’s television news-

casts include a new and more disturbing episode of pharmacological crisis and
medical mayhem in the United States” (Markel, 2005).
“. . . FDA has become synonymous with drug safety. In a sense, ‘FDA ap-
proved’ is the brand that the entire $216 billion US drug market is founded
upon. Dilute the confidence of the public in the agency, and many billions of
dollars in current and potential sales vanish overnight. That’s exactly what’s
happening right now in the wake of the biggest drug withdrawal ever” (Herper,
2005).
The recent highly publicized controversies surrounding the safety of

some drugs have contributed to a public perception that the drug safety
system is in crisis. It seems fair to say that this perception has created an
opportunity for a thorough evaluation of the US drug safety system. News
media coverage and congressional examination of the Center for Drug
Evaluation and Research’s (CDER’s) handling of safety concerns have raised
questions about the review and approval process and whether it has become
so accelerated that adequate attention may not be given to safety, and about
the completeness and timeliness of risk communication to the public. Ques-
tions also surfaced about the independence of the scientific expertise relied
on by the Food and Drug Administration (FDA) (conflict of interest in its
advisory committees) and about the possibility of undue industry influence
related to CDER’s increasing dependence on Prescription Drug User Fee
Act (PDUFA) funding. It would be easy to conclude that FDA’s most recent
troubles are just a reflection of the swinging of the pendulum from tighter
to looser regulation and back again (Applebaum, 2005; Geraghty, 2006).
The committee believes that the reality is more complicated than that. The
committee did not attempt to document whether or not a drug safety crisis
exists, and this report should not be interpreted as commenting on that
claim one way or the other. The committee also did not set out to—nor
was it asked to—conduct in-depth reviews of the industry and the agency’s
handling of safety information and data for drugs with potential safety
problems. Instead, the committee examined the existing drug safety system
15

with a view to identify areas of vulnerability and facets of the system that
could be strengthened in order to improve its overall functioning in meeting
the needs of the American public.
Complaints about delayed patient access to drugs already approved
in other countries and the AIDS advocacy movement of the 1980s are
considered among the major factors that motivated legislative action to
speed up FDA’s drug approval process. However, criticism of the pace of
drug approval may be traced to the early 1970s. At that time, pharmaceu-
tical companies, scientists, and consumer organizations argued that the
1962 Drug Amendments to the Food, Drug, and Cosmetic Act, intended
to strengthen the drug approval process by requiring that sponsors dem-
onstrate efficacy, also stifled drug development and delayed drug approval
(DHEW, 1977). In the 1990s, FDA attributed the delays to shortages of
staff and computers (FDA, 2005b). Concern about the slow pace of drug
review finally led to PDUFA.
The enactment of PDUFA in 1992 resulted from a potent combination
of interests. Patient advocacy groups called for faster access to promising
therapies, the industry desired a more efficient regulatory process to enable
faster marketing of new drugs and a longer patent life, FDA needed more
resources to expand its review staff to meet demand for greater regulatory
expediency, and some members of Congress were concerned that new drug
approvals in the United States lagged behind those of comparable European
nations. With congressional oversight and input, PDUFA was enacted with
the goal of meeting the needs of FDA, industry, and patients. Although the
1992 PDUFA succeeded greatly in decreasing review times (FDA, 2005b),
its first two iterations (PDUFA I in 1992 and PDUFA II in 1997, see below)
specifically prohibited the use of fees for any postmarketing drug safety
activities. Also, the speeding up of the review process highlighted poten-
tial weaknesses and limited capability in the area of postmarketing safety.
By the latter part of the 1990s, various observers, including consumer
groups and researchers, became concerned that the increased pace of drug
approvals had unintentionally led to a neglect of—or at least insufficient
attention to—safety considerations, resulting in what was seen as a greater
rate of drug withdrawals (Lurie and Wolfe, 1988; Hart, 1999; Tone, 1999).
Numerous journal editorials and articles by scientists, consumer advocates,
and agency leadership continued the dialogue (Kleinke and Gottlieb, 1998;
Wood et al., 1998; Friedman et al., 1999; Landow, 1999; Lurie and Sasich,
1999). In response to mounting unease, FDA Commissioner Jane Henney
convened “a Task Force to evaluate the system for managing the risks of
FDA-approved medical products” (DHHS/FDA, May 1999). Although
the task force found that rates of withdrawals were low (the limitations
of treating withdrawals as a safety metric are discussed below), the group
identified process, resource, and statutory constraints on FDA’s ability to

INTRODUCTION 17
identify adverse events and made a series of substantive recommendations to

strengthen risk management. Some of the recommendations of the task force
have been implemented, including the convening of public meetings to solicit
input on drug safety and risk management from various constituencies.
Drug safety concerns have continued to emerge, as have the proposals
to address them. Alosetron was withdrawn and then returned to market
with restrictions and a label warning. Troglitazone, propulsid, cerivastatin,
rofecoxib, and valdecoxib have been withdrawn. Celecoxib and other non-
selective non-steroidal anti-inflammatory drugs had boxed warnings added
to their labels. Warnings have been added to all antidepressant labels. FDA’s
performance in approving drugs or monitoring their safety after approval
has been questioned and criticized. Several major factors converged to create
at the least the appearance of a crisis in drug safety, among them, CDER’s
limited resources, organizational and management challenges, seemingly
long reaction times, poor external communication, questions about external
influences on CDER’s decision making, an ever more diverse information
environment (news media, the Internet and the blogosphere, and advertis-
ing) coupled with increasing consumer awareness and engagement, and
growing congressional concern.
The Committee on the Assessment of the US Drug Safety System be-
lieves that as more drugs are being approved faster with less time to inten-
sively investigate premarketing safety data, FDA does not have adequate
resources or procedures for translating preapproval safety signals into ef-
fective postmarketing studies, for monitoring and ascertaining the safety of
new marketed drugs, for responding promptly to the safety problems that
are discovered after marketing approval, and for quickly and effectively
communicating appropriate risk information to the public. The committee is
aware of promising components of the current drug safety efforts at CDER
and of agency improvement initiatives (see Appendix A), but it believes
that neither the agency’s newly enhanced postmarketing safety initiatives
nor the necessary contributions of other actors in the US drug safety system
are equal to the task. Major obstacles remain. They include inadequate
resources, the complexity of the science and technology involved in drug
development and regulation (e.g., assessing risk and benefit), a dysfunctional
organizational culture, problems with credibility and public trust, and the
lack of adequate communication about and limited public awareness of
drug risks and benefits.
The credibility of FDA, the industry, the academic research enterprise,
and health care providers has become seriously diminished in recent years
(Kaiser Family Foundation, 2005; Wall Street Journal and Harris Interac-
tive, 2005). FDA’s reputation has been hurt by a perceived lack of transpar-
ency and accountability to the public, a legacy of organizational changes
that have not been completed or sustained, and an apparent slowness in

addressing lack of sponsor compliance (US House of Representatives Com-

mittee on Government Reform Minority Staff, 2006). The industry’s once
sterling reputation has been blemished by reported compliance problems,
delays in responding to safety concerns and complying with postmarketing
commitments, highly publicized concerns about the effects of direct-to-
consumer advertising, and the preponderance of “me-too” products, rather
than truly pioneering therapies (PricewaterhouseCoopers Health Research
Institute, 2005; Wall Street Journal and Harris Interactive, 2005). The
integrity of the academic research enterprise has also been questioned, as
universities and scientists are increasingly dependent on industry funding for
their work. The behavior of prescribers, the gatekeepers for patient access
to prescription drugs, are also under public and congressional scrutiny, as
health care providers receive intense and targeted promotional (“detailing”)
efforts of pharmaceutical companies.
Of particular concern are the common but inaccurate perceptions that
FDA approval represents a guarantee of safety, that approval is based on a
high degree of clarity and certainty about a drug’s risks and benefits, and
that such safety actions as boxed warnings on drug labels and withdrawals
reflect sponsor or agency failures.
Addressing weaknesses and missed opportunities in the drug safety
system requires some fundamental changes in the organizational culture of
CDER to support effective action on drug safety (Chapter 3), in the scientific
approaches to drug safety (Chapter 4), in the regulations pertinent to drug
safety (Chapter 5), in communication about drug safety (Chapter 6), and
in the agency’s funding structure (which currently leaves critical regulatory
and public health functions inadequately resourced) (Chapter 7).
Some of the recommendations offered in this report echo proposals
made over the last two decades by various groups convened by the agency
or by the Department of Health and Human Services (DHHS) (DHEW
Review Panel on New Drug Regulation, 1977; Joint Commission on Pre-
scription Drug Use, 1980; DHHS/FDA, 1999). It is puzzling and troubling
that despite this series of reviews and recommendations, some have not been
fully implemented and some issues have resurfaced repeatedly. A primary
obstacle, the committee suspects, may be the chronic underfunding of core
FDA activities owing to inadequate attention to resource needs by Congress
and by the Office of Management and Budget. The committee asserts that
the piecemeal organizational modifications and short-lived programmatic
initiatives of the past and the current, seemingly fragmented and reactive
initiatives to improve CDER are not sufficient to meet the need to improve
postmarket drug safety activities and protect the public health better. The
present report endeavors to provide an integrative approach to transforming
drug safety in FDA and in the agency’s interactions with other stakeholders

INTRODUCTION 19
in five major areas: organizational culture and leadership, science, regulatory

authority, communication, and the funding without which improvements in
these areas would not be possible. No one in FDA, industry, or academic
research enterprise would disagree with the importance of implementing a
lifecycle approach to the assessment of drug risks and benefits. Neverthe-
less, a great deal of separation persists between premarket and postmarket
activities and functions. The separation, both structural and cultural, is
reinforced by user-fee funding that is predominantly devoted to premarket
activities and funding from appropriations that has not kept up with need
in vital areas of the agency’s work, by regulatory authority that is stronger
and clearer preapproval, and by data requirements that are more structured
and intensive for approval than for the postmarketing period (see Chapter
3) (DHEW Review Panel on New Drug Regulation, 1977; FDA, 2005b).
The year 2006 is a good time for thoughtful attention to transform-
ing the drug safety system to address existing areas of vulnerability, and
to prepare for the challenges and opportunities of the future. In this year
of FDA’s centennial, public attention to drug safety matters has reached a
high point, negotiations in advance of the September 2007 sunset of PDUFA
have begun, Medicare Part D has enrolled tens of millions of senior citizens
in a system that is expected to yield a wealth of population data about ex-
perience with drugs, new research promises further progress against illness
(including more targeted therapies), and congressional interest in drug safety
is intense. Those are but some of the factors that make this a moment of
opportunity to renew and transform CDER, to enable it to function more
effectively and to position itself for a far more complex future.
Changes in the Broad Context of Drug Regulation

Prescription drug development, regulation, and use have changed
greatly since the 1962 drug amendments and continue to evolve. The
scientific and demographic changes of the future will present challenges
and opportunities for drug development and regulation. The promise of
personalized medicine shimmers on the horizon, but considerable work
remains to identify candidate measures, validate them, and show that their
use in a clinical setting improves health outcomes, reduces costs, or both.
The population of the United States is aging and requires more therapeutics
for prevention and treatment for the chronic diseases associated with older
people. Increasing ethnic and cultural diversity will require better under-
The year 2006 is technically the centennial of the 1906 Pure Food and Drug Act, but the
FDA asserts that “the modern era of the FDA dates to 1906 with the passage of the Federal
Food and Drugs Act” (CDER, 1998).

standing of disparities in health status and the development of appropriate

means of communicating useful therapeutic and health care information to
heterogeneous populations.
The science and technology that underpin drug discovery are in a
process of dramatic transformation. Advances in the basic sciences have
increased the number of targeted drugs, and technological advances promise
to transform and expand the array of drugs available for the prevention and
treatment of human disease (Gwynne and Heebner, 2001; Cockburn, 2004).
Technologic and scientific developments also promise to enhance the predic-
tion of safety problems and opportunities earlier in the development process,
but much more work is needed to actualize these promises (FDA, 2004).
The practice of drug discovery and drug development research has also
changed substantially in response to scientific and technological advances.
Drug discovery research is funded by both industry and government, and
takes place in academe, government—especially the National Institutes of
Health (NIH)—and industry. Almost all drug development occurs in indus-
try, but an increasing proportion of industry-funded studies is being con-
ducted outside academic health centers by contract research organizations,
and more clinical trials are being conducted abroad (Cockburn, 2004).
Biomedical research accounts for 5.6 percent of health expenditures in the
US, with 57 percent of the research is funded by industry, and 28 percent
by NIH (Moses et al., 2005). Despite advances, the development of new
pharmaceutical problems is facing challenges—in its Critical Path report
(FDA, 2004), FDA asserted that the translation from the basic sciences of
drug discovery to the applied sciences of drug development has become slug-
gish because “the development path is becoming increasingly challenging,
inefficient, and costly.”
The practice of medicine and the provider-patient interaction—the point
where the pharmaceutical product traditionally “meets” the patient—also
have undergone great transformation in the last two or three decades. First,
use of prescription drugs has been increasing steadily (Ganslaw, 2005).
Physicians and other health care providers have more therapeutic options at
their disposal, and both polypharmacy and the chronic use of drugs have
become extremely common, especially in the rapidly growing segment of the
population in late middle age and older. Use of drugs to treat chronic disease
risk factors such as high blood pressure and high cholesterol has expanded
immensely. Second, the role of the patient has changed as part of the larger
shift toward consumer empowerment in the private sector. The health care
system (like other sectors) places increased emphasis on consumer choice.
The administration of multiple drugs concurrently, with the concomitant increased risk of
drug interactions.

INTRODUCTION 21
Quality of care also has become a major issue for consumers. Pharmaceuti-
cal and health plan offerings are promoted to consumers now empowered
to be decision-makers. Patients have unprecedented access to information
about drugs, their benefits, and side effects. This is due in part to changes in
the information environment. Promotion of drugs to patients has increased,
including broadcast direct-to-consumer advertising. Access to the Internet
has become widespread; this powerful tool provides access to information
that varies greatly in accuracy, quality, and completeness (Tatsioni et al.,
2003). The relationship between patients and their physicians has changed
as patients have become more engaged and knowledgeable. Third, a cat-
egory of “lifestyle” drugs has arrived in the marketplace. Two decades ago,
patients used drugs chronically for treatment for and control of serious
diseases. Today, many fundamentally healthy people take drugs long-term
for purposes ranging from cosmetic improvement (such as botox) to symp-
tomatic management (such as antihistamines) to performance enhancement
(such as erectile dysfunction). For people who need to take drugs for control
or treatment of serious diseases, the potential of adverse drug effects may
be of less concern than it is for people who take drugs for very minor issues
(see Box 1-1 for some FDA milestones).
Defining and Meeting the Charge

The Charge
Given the changes outlined above and in response to growing public

concern with health risks posed by prescription drugs, FDA requested that
the Institute of Medicine (IOM) convene an ad hoc committee of experts
to conduct an independent assessment of the current system for evaluating
and ensuring drug safety and to make recommendations to improve risk
assessment, surveillance, and the safe use of drugs (see Box 1-2). In recogni-
tion of their roles in the drug safety system, the Centers for Medicare and
Medicaid Services (CMS), the Agency for Healthcare Research and Quality
(AHRQ), NIH, and the Department of Veterans Affairs are also sponsors
of the report.
In responding to the charge, the committee focused much of its attention
on FDA’s CDER. Although the report is addressed to the FDA as a whole,
a considerable proportion of the committee’s discussion and recommenda-
tions pertain to CDER’s structure, organization, and scientific and regula-
tory activities. Given the study timeframe, the committee found it difficult
to accord the same level of attention (in terms of a detailed assessment and
recommendations) to all other important stakeholders in the drug safety
system. The roles of industry, the health care delivery system, and health care

BOX 1-1
Some Key Milestones in FDA History
The Pure Food and Drug Act of 1906 gave FDA’s predecessor, the Bu-
reau of Chemistry in the Department of Agriculture, its first regulatory powers.
At inception, the agency’s pharmaceutical regulatory work focused largely on
misbranding and adulteration of drugs. In 1937, elixir sulfanilamide caused
more than 100 deaths and led to the passing of the 1938 Federal Food, Drug,
and Cosmetic (FD&C) Act. The act prohibited false therapeutic claims for drugs
and for the first time required premarket notification of FDA by the sponsor for
all new drugs. This meant that a company submitted its New Drug Applica-
tion (NDA) and, if FDA did not explicitly prohibit marketing, the company was
free to market the product without any type of approval after 60 days (unless
FDA extended that period to 180 days), when the NDA became “effective.”
Although the FD&C Act required a manufacturer to prove a drug’s safety by
conducting preclinical toxicity testing and gathering and submitting drug safety
data, it did not require proof of efficacy (Swann, 1998; Stergachis and Hazlet,
2002). Some two decades later, thousands of children with birth defects were
born to European mothers who had taken the popular sedative thalidomide
for morning sickness. Marketing of thalidomide in the United States had been
held up in the approval process and this so-called near miss led to the Drug
Amendments of 1962. The drug amendments required companies to provide
proof of efficacy of a drug for it to be considered for marketing approval, and
the randomized controlled trial became established as the gold standard for
demonstrating efficacy (Stergachis and Hazlet, 2002).
In the 1980s, the public health crisis of HIV/AIDS motivated a powerful
advocacy movement whose aims included faster approval of drugs for patients
with incurable disorders. Other consumer and patient advocacy groups began
to call for changing the drug approval process to speed up the availability
of potentially life-saving or life-sustaining drugs to patients in need of them.
Consumer groups, regulators, the regulated industry, and others contributed
to and Congress passed the PDUFA legislation that aimed to ensure that FDA
had adequate resources to expand its drug review staff and capabilities, and
so to increase the pace of drug reviews. Agreements among FDA, industry,
and Congress are crystallized in a series of performance goals for FDA. These
are not part of the PDUFA statute, so they lack the force of law (Tauzin, 2002)
but they reflect activities the agency considers its obligations—“The letter out-
lines goals that the agency must meet, which help frame the basis to judge the

INTRODUCTION 23
user fee programs success” (Tauzin, 2002). These goals are contained in the
“PDUFA Reauthorization Performance Goals and Procedures,” or the PDUFA
“goals letter” (a letter with enclosures), which is transmitted by the Secretary
of HHS to Congress annually.
PDUFA required that FDA and specifically CDER review staff meet cer-
tain performance goals and report annually to Congress on their progress in
meeting those goals. PDUFA also required that companies pay three types of
fees to FDA, including a one-time fee submitted with each NDA, an establish-
ment fee, and a product fee (FDA, 2005a,b).* Congress reauthorized PDUFA
in 1997 (as part of the FDA Modernization Act) and in 2002 as part of the
Bioterrorism and Preparedness and Response Act. In PDUFA I and II, funds
were limited to use to the review of sponsor applications for new drugs and
indications. No PDUFA funds were allocated to postmarketing drug safety
activities until 2002, when limited funds were allocated for limited safety activi-
ties. The 1992 PDUFA Amendments to the FD&C Act stipulated that PDUFA
user fees must not be used in lieu of but to supplement appropriations. FDA
was authorized to assess user fees only if appropriations for drug review were
equal to or greater than appropriations for salaries and other FDA expenses
in 1992 (Zelenay, 2005). PDUFA II set the trigger at 1997 levels: “Fees under
subsection (a) of this section shall be refunded for a fiscal year beginning after
fiscal year 1997 unless appropriations for salaries and expenses of the Food
and Drug Administration for such fiscal year (excluding the amount of fees
appropriated for such fiscal year) are equal to or greater than the amount of
appropriations for the salaries and expenses of the Food and Drug Admin-
istration for the fiscal year 1997 (excluding the amount of fees appropriated
for such fiscal year) multiplied by the adjustment factor applicable to the
fiscal year involved” (21 US Code 379h(f)). The adjustment factor is based on
the Consumer Price Index (Zelenay, 2005), and that may help explain why,
although the agency has always met the trigger that allowed the collection of
user funds, appropriations have grown at a much lower rate than user fees
(FDA, 2005b). Appropriations have not only not kept pace, but they have
declined since 2003, as FDA’s payroll costs have increased (FDA, 2005b).
*For FY 2006, the application fee is $767,400, the establishment fee is $264,000,
and the product fee is $42,130 (FDA, 2005a).

BOX 1-2
The Statement of Task
In response to growing public concern with health risks posed by
approved drugs, the FDA has requested that the IOM convene an ad
hoc committee of experts to conduct an independent assessment of the
current system for evaluating and ensuring drug safety postmarketing and
make recommendations to improve risk assessment, surveillance, and the
safe use of drugs. As part of its work, the IOM committee will:
• examine the FDA’s current role and the role of other actors (e.g.,
health professionals, hospitals, patients, other public agencies)
in ensuring drug safety as part of the US health care delivery
system;
• examine the current efforts for the ongoing safety evaluation of
marketed drug products at the FDA and by the pharmaceutical
industry, the medical community, and public health authorities;
• evaluate the analytical and methodological tools employed by
FDA to identify and manage drug safety problems and make
recommendations for enhancement;
• evaluate FDA’s internal organizational structure and operations
around drug safety (including continuing postmarket assessment
of risk vs. benefit);
• consider FDA’s legal authorities for identifying and responding to
drug safety issues and current resources (financial and human)
dedicated to postmarketing safety activities;
• identify strengths, weaknesses, and limitations of the current
system; and
• make recommendations in the areas of organization, legislation,
regulation, and resources to improve risk assessment, surveil-
lance, and the safe use of drugs.
providers, patients, the public, Congress, the academic research enterprise,

and other government agencies are discussed in much less detail. However,
the committee’s recommendations have implications for those stakeholders,
and are discussed in the report where appropriate.
What This Study Is Not
This report does not address the related area of medication errors. That
was the purview of the IOM Committee on Identifying and Preventing
Medication Errors, whose report was released July 2006 (see Appendix E

INTRODUCTION 25
for that report summary). The present report does not treat several very
important issues that were not in the charge given to the committee, includ-
ing the regulation or safety of medical devices or biological products other
than those regulated by CDER; pharmaceutical product abuse, overuse, or
misuse; over-the-counter (OTC) drugs or the switch from prescription to
OTC status; generic drugs; drug pricing; or the causes and consequences of
the current challenges in pharmaceutical innovation. Finally, although the
postapproval stage of a drug’s life cannot be discussed in isolation from the
preapproval stages, this report does not consider in any detail the complex
ethical, practical, economic, and scientific issues related to the Investigation-
al New Drug process or the clinical trial conduct in the testing of drugs.
Study Process
The committee gathered information to address its charge through a

v ariety of means. It held three information-gathering meetings and one
workshop that were open to the public. The first meeting focused on ob-
taining background on the committee charge from a number of perspec-
tives, including FDA’s. This and all other meeting agendas can be found in
Appendix D. The second meeting focused on hearing from the public on
day 1, and learning about the role of FDA, AHRQ, and CMS in US drug
safety activities on day 2. The committee also held a workshop on Advancing
the Methods and Application of Risk-Benefit Assessment of Medicines and
held a final information-gathering meeting to hear opinions on proposals to
improve drug safety in the United States. The committee met in executive
sessions for deliberative discussions throughout the study process.
All the open meetings were Webcast in real time so that members of the
public could listen to the proceedings and send questions to the committee
by e-mail. The committee also received public submissions of material for its
consideration at the meetings and by mail, e-mail, and fax throughout the
course of the study. A Web site (http://www.iom.edu/drugsafety) and a list-
serv were created to provide information to the public about the committee’s
work and to facilitate communication with the committee. Many of the
speakers’ presentation slides from the three information-gathering meetings
and workshop are available in electronic format on the project’s Web site.
A few committee members and staff visited FDA to gain a better under-
standing of the background and daily operations of CDER. The committee
and staff also conducted over 30 discussions with present and past FDA
staff, managers, and leadership. Those discussions were confidential, but
a summary of the main themes and points of discussion is provided in the
public access file for this project (see IOM Staff Notes, 2005–2006).
The committee also commissioned two papers to inform it about
industry’s views of drug safety in the United States (written by Hugh Tilson)

and those of academe (written by Brian Strom); these papers were based in
part on small meetings convened by the authors and can be found in the
public access file.
Moving Target—The Shifting Landscape of Drug Safety in the

United States
The committee has worked in the context of continuing change and

proposals for change: modifications in the organizational structure of CDER
and in the evaluation and monitoring of drug safety undertaken by FDA
and to a lesser extent other stakeholders; multiple legislative proposals for
changing the structure, resources, and authorities of CDER in FDA; and
consumer and patient organizations’ calls for changes in CDER. Those ef-
forts have, in some cases, informed the work of the committee during its
deliberations. Some of these changes have closed gaps, others have raised
new questions and concerns, and still others have helped to increase the
knowledge base of the committee. The efforts are described in greater detail
in Appendix A.
Toward a New Vision of Drug Safety
The increasingly complex interface between innovation and regula-

tion has been characterized by binary opposites: speed vs. safety, tight
preapproval regulation vs. loose postapproval regulation, active collec-
tion of data before approval vs. passive surveillance after approval, and
an abundance of clinical efficacy data before approval compared to much
fewer safety data after approval. The polarity of approach and emphasis is
inconsistent with the widely accepted notions that risk must be considered
in the context of benefits, that understanding of the risks and benefits as-
sociated with a drug changes over a drug’s lifecycle (FDA, 2004), and that
the attention paid to safety and efficacy before approval must therefore be
sustained as a drug enters and diffuses through the market and is used by a
growing number and diversity of patients. Timely approval and attention to
safety can become complementary rather than antithetical goals as postap-
proval surveillance becomes more effective, and regulatory authority and its
exercise is commensurate with how a drug performs in real-life conditions
over its lifecycle.
A list of materials reviewed by the committee (in the form in which they were reviewed),
including all submissions of information from the public and many items not cited in this
report, can be found in the study’s public access file, obtained from the National Academies
Public Access Records Office at (202) 334-3543 or http://www8.nationalacademies.org/cp/
ManageRequest.aspx?key=162.

INTRODUCTION 27
The approval decision does not represent a singular moment of clarity

about the risks and benefits associated with a drug—preapproval clinical
trials do not obviate continuing formal evaluations after approval. However,
the approval decision is a critical juncture in a product’s lifecycle because it
releases a drug to the market, where the public will gain broad exposure to
it. In a strengthened drug safety system, that juncture should mark the begin-
ning of another important stage in the lifecycle, when regulators, sponsors,
health insurers, health care providers, and independent researchers actively
pursue and manage emerging knowledge about risk-benefit relationships
and uncertainty and they communicate that knowledge to patients, and
health care organizations in a timely manner. Regulatory, health insur-
ance coverage, and treatment decisions over a drug’s lifecycle depend on
the quality and timeliness of data collected, evaluated, and transmitted by
trustworthy stakeholders in the health care system. In short, a drug safety
system oriented around the new paradigm requires:
• A culture of safety in CDER supported by strong leadership, effec-

tive management, science-based decision making that is, insofar as
possible, insulated from outside influences, and a healthy organiza-
tion that encourages debate, teamwork, and independent scientific
inquiry.
• Science that is rigorous and that through the individual and joint
efforts of sponsors, academic researchers, and health care organi-
zations describes a drug’s risk-benefit profile, patterns of drug use,
comparative effectiveness of drugs, behaviors of prescribers and us-
ers, and behaviors of institutions that affect prescribers and users.
• A regulatory process that is flexible, dynamic (e.g., proactive, respon-
sive), and attentive to safety throughout the lifecycle of a drug, and
a regulatory agency that is sufficiently empowered to take actions
necessary to protect the public health.
• Communication about safety that is timely and effective and that
facilitates transparency and enhances credibility.
The committee’s vision of a transformed drug safety system has at its

core a lifecycle approach to drug risk and benefit—not a new concept, but
one that has been implemented, at best, in a narrow and fragmented man-
ner. For FDA, attention to risk and benefit over the life of a drug requires
continuous availability of new data and ongoing, active reassessment of
risk and benefit to drive regulatory action (in response to the accumulating
information on a given drug), and regulatory authority that is strong both
before and after approval. For the industry, attention to risk and benefit over
the lifecycle will require more careful assessments of emerging information
about possible new risks and timely communication of this information to

FDA, and acceptance of changes intended to strengthen drug safety. FDA’s

credibility is intertwined with that of the industry, and a more credible
drug safety system is in everyone’s best interest. For the health care delivery
system, a lifecycle approach to risk and benefit implies the need to heed
and follow FDA communication about drug safety matters and to exercise
appropriate caution in drug-related decision making (from formularies to
prescribing) in recognition of the limited information available at the time
of drug approval. The health care delivery system will benefit by consistently
basing prescribing decisions on the science, and by exercising caution in
regard to the industry’s influence on the practice of medicine. Health care
organizations and professional societies can contribute to prescribers’ un-
derstanding of the evolving science behind the assessment of drug risk and
benefit. The academic research enterprise can enhance its contributions of
data to the assessment of risk and benefit at all points in a drug’s lifecycle,
continue its crucial advisory relationship with FDA, and uphold the value
of complete transparency in recognition of real and perceived conflicts as-
sociated with financial involvement with the industry. Other government
agencies can contribute to the lifecycle approach to drug risk and benefit by
collaborating with FDA and the private sector to ensure that data streams
from publicly funded health care settings contribute to an improved drug
safety system. The public and patients can do their part by communicating
with their health care providers about the pharmaceutical products they are
using, learning about and discussing with their providers a drug’s risks and
benefits in the context of their health needs and characteristics, informing
their providers about side effects they experience, and calling for more use-
ful and timelier information about drug benefits and risks associated with
new drugs.
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Natural History of a Drug
This chapter describes some key steps in reviewing potential new

therapies and monitoring drugs once they are in the marketplace, with an
emphasis on how safety considerations are handled throughout the pro-
cess. The elements of the drug regulatory system have been well described
elsewhere (Lipsky and Sharp, 2001; Randall, 2001; Meadows, 2002; FDA,
2006c). The committee also reviewed some of the factors that shape how
the understanding of a drug’s safety and efficacy profile evolves during the
lifecycle and what regulatory action is taken. Those factors include scientific
uncertainty; resources at the Food and Drug Administration (FDA); statu-
tory requirements, including both limitations in authority and deadlines
that shape the timing and scope of regulatory activities; and workload and
staffing.
This discussion is intended to provide a reference point for subsequent
chapters that provide the committee’s findings about the strengths and weak-
nesses of the drug safety system and recommendations for strengthening it.
A number of the points addressed in this chapter are related directly to the
committee’s recommendations. The material in this chapter is drawn largely
from Center for Drug Evaluation and Research (CDER) documents—both
guidance documents for sponsors and internal manual of policies and
procedures that describe a wide variety of official policies—and from con-
versations with current and former FDA staff.
CDER reviews various types of drug applications and supplements.
This chapter focuses on New Drug Applications (NDAs), although some
of the processes also apply to supplemental NDAs, which are most often
submitted for new indications of approved drugs. The chapter traces the
31

work of the NDA review process in CDER’s Office of New Drugs (OND)
and its offices of drug evaluation which conduct premarket reviews, and
in CDER’s Office of Drug Safety (ODS) (which is now called the Office of
Surveillance and Epidemiology, OSE, because of a restructuring of CDER
in May 2005) and its Division of Drug Risk Evaluation (DDRE), which
monitors postmarket risks and undertakes risk assessments. (Other divisions
and offices of ODS/OSE address safety issues, such as medication errors and
drug names.) The chapter does not address Abbreviated NDAs for generic
drugs that go through CDER’s Office of Generic Drugs. Nor are drugs that
are on special tracks, such as accelerated approval or orphan-drug status,
specifically addressed in this general description of how a new drug moves
through the system.
Economic Impact of Drugs

Prescription drugs play a major role in American health and economy.
For example, prescription drugs for controlling blood pressure and blood
cholesterol levels were partly responsible for one of the ten great public
health achievements of the 20th century: the 5 percent decline in death rates
for coronary heart disease since 1972 (CDC, 1999). Prescription drugs are
among the innovations that have replaced some highly invasive measures
(such as surgery) with less invasive preventive and health maintenance
therapies (DHHS, 2002). Prescription drugs also can help reduce health
care costs by decreasing hospitalization. National survey data show that 44
percent of Americans take at least one prescription drug in any given month
(NCHS, 2004). In economic terms, the investment and return on investment
of drug discovery and development are vast. Although methodologies used
for estimating the cost of bringing a drug to market are a matter of some
controversy, some estimates are provided here as an illustration (Epstein,
2004). The cost of drug development has been estimated at approximately
$800 million and at between $500 and $2,000 million (DiMasi et al., 2003;
Adams and Brantner, 2006). The Bain report provided the estimated cost of
development at $1.7 billion (Gilber et al., 2003). In 2005, the biopharma
ceutical industry spent approximately $51.3 billion in drug discovery and
development (PhRMA, 2006). A great deal is spent on prescription drugs.
Due to cost-containment strategies, the rate of increase of spending on pre-
scription drugs has slowed down, but still totaled $179.2 billion in 2003,
and comprised 11 percent of national health spending (Kaiser Family Foun-
dation, 2005; Smith et al., 2005).
For the remainder of this chapter, we will refer to this office as ODS/OSE.
Division of Surveillance, Research and Communication Support and Division of Medication
Errors & Technical Support.

NATURAL HISTORY OF A DRUG 33
THE INVESTIGATIONAL NEW DRUG

As discussed in Chapter 1 and throughout the report, FDA has initiated
or is initiating many changes related to drug safety in its internal procedures
and organization. Some of the changes may supersede the descriptions in
this chapter. Also on the horizon is FDA’s Critical Path Initiative, announced
in 2004, which is intended to stimulate the development and use of new
scientific tools to better assess the safety and effectiveness of drugs under
study (FDA, 2004a; DHHS/FDA, 2006).
Investigational New Drug Submission and Review

The vast majority of chemical molecules and candidate drugs screened
for therapeutic potential and toxicity never show sufficient promise to enter
human trials (PhRMA, 2006). But when preclinical data indicate that a
compound is reasonably safe for initial testing in humans, shows promising
pharmacologic activity, and has commercial prospects, the sponsor submits
an Investigational New Drug (IND) Application to FDA, and the agency’s
oversight begins (FDA, 2006c).
IND sponsors can be companies, research institutions, or individual
investigators. Often the sponsor has been in frequent contact with FDA
throughout the development process prior to submission of the IND, and
has participated in FDA’s pre-IND consultation program (FDA, 2006c).
FDA produces numerous guidance documents to steer sponsors through the
regulatory process. Those documents are prepared and updated continu-
ally. Some are very specific, for example, describing appropriate methods
for a specific type of study; others provide more general guidance about
preparing submissions to the agency (FDA and CDER, 2006b). Some reflect
international harmonization efforts among European, Japanese, and US
regulators.
The average new commercial IND submission totals about 28 vol-
umes of about 500 pages each—about 14,000 pages (Henderson, 2006).
It contains manufacturing and chemical information about the drug and
the results of animal tests, toxicology studies, and other preclinical tests.
The IND also contains protocols for small phase 1 human studies intended
to document the drug’s metabolism and excretion, determine a safe dose,
and identify acute side effects (FDA and CDER, 2006b). Local institutional
review boards (IRBs) must review the protocols to ensure protection of
human subjects. If a sponsor has already begun human trials outside the
United States, it also includes their results.
By law, FDA has 30 days from the date an IND is received to place a
hold on the proposed human trials (FD&C Act, SEC. 505(i)(2)) if it deems
it to be necessary. CDER can take up to about 2 weeks of that period to
process the IND, assign it to a review division within OND on the basis of

the drug’s likely indication, and assemble a review team. The team includes
a project manager and several scientific reviewers from OND and other
CDER offices as required (CDER et al., 1998). The reviewers then have the
remainder of the 30-day period to determine whether safety concerns justify
placing a hold on the human trials. In the absence of FDA action to delay
or prevent a trial, the sponsor can begin testing the compound in humans
on day 31 (FDA and CDER, 2006b).
FDA typically allows human trials to proceed if no serious safety con-
cerns have surfaced (FDA and CDER, 2001a). As occurs throughout the
review process, safety assessments and regulatory actions are influenced by
evidence of the potential benefit of the product. For example, reviewers are
likely to tolerate a higher threshold of toxicity for a drug that will be used
to treat life-threatening cancer than for a new antihistamine similar to those
on the market.
Early Clinical Trials and Related Studies
The sponsor typically begins phase 1 trials by testing several increasing

dosages in healthy volunteers (see Box 2-1 for definitions of all phases of
clinical trials). About 20–80 subjects are usually involved in one or more of
these trials (FDA, 2006c). Animal and other toxicology studies and phase 1
studies may be concurrent. If the initial phase 1 results do not show unac-
ceptable toxicity, the sponsor moves to larger, phase 2, trials which involve
from a few dozen to hundreds of patients who have the condition for which
the drug is being studied (CDER et al., 1998; FDA, 2006c). Efficacy and
safety are evaluated by continuing to test various dosages of the compound
in patients (FDA, 2006c).
Clinical trials are conducted under the sponsor’s auspices by com-
mercial, academic, or other entities in the United States or, increasingly,
overseas. In trials, an active product is compared with a placebo or oc-
casionally with an existing drug for the condition (FDA, 2006c). Sponsors
increasingly include genetic studies in the premarket period as part of a
personalized-medicine approach to identifying target populations for a drug.
The developing science of pharmacogenomics is generating strong interest
and attention in and outside FDA as a way to improve drug safety through
predictive techniques, but any widespread use of these techniques in clinical
practice is well into the future.
Sponsors develop study protocols and undertake, fund, and oversee
studies. The OND review team and sponsor consult as the trials and stud-
ies are under way, new protocols are developed, and new data emerge. The
review team can play a critical role in how the studies proceed. The extent
of consultation varies among drugs and sponsors. The sponsor is required
to notify FDA and all investigators in written safety reports of “any adverse

BOX 2-1
Phases of Clinical Trials and Medicine Development
Phase 1
Clinical pharmacology studies in healthy volunteers (sometimes subjects)
to determine the safety and tolerability of the drug/product, other dynamic
effects, and the pharmacokinetic profile (absorption, distribution, metabo-
lism, and excretion).
Phase 2
Clinical investigation studies in subjects with the target disease, to
determine efficacy, safety, and tolerability in carefully controlled dose-
ranging studies. Phase 2 studies are typically well controlled and closely
monitored.
Phase 3
Formal clinical trials. Large-scale placebo controlled and uncontrolled
studies in subjects to gather further information on efficacy and on the
safety and tolerability of the drug or product.
Phase 4
Postmarketing surveillance to expand safety and efficacy data in a large
population, including further formal therapeutic trials and comparisons
with other active comparators.
SOURCE: Adapted from 21 CFR 312.21 (2005).
experience associated with the use of the drug that is both serious and un-
expected” or “any finding from tests in laboratory animals that suggests a
significant risk for human subjects including reports of mutagenicity, tera-
togenicity, or carcinogenicity” (21 CFR 312.33). The sponsor also submits
annual progress reports on the IND to FDA.
The regulators may direct the sponsor to undertake specific studies
or laboratory evaluations in studies to look for possible markers of safety
problems (such as liver toxicity or cardiovascular changes) on the basis of
previous experience or questions about the class of drugs or the mechanism
of action.
End of Phase 2 Meeting and Phase 3 Trials
If the results of the early trials are promising, the sponsor and the review
team typically meet for an “end of phase 2 meeting” to discuss the upcom-

ing phase 3 trials. The phase 3 trials can involve fewer than 100 patients in
some cases or many thousands in others, depending on the target popula-
tion and the endpoints being evaluated (on the average, they involve about
600–3,000 patients). The drug is tested against a placebo or sometimes
against another drug (FDA, 2006c). The trials are designed and powered
to evaluate selected efficacy outcomes, not safety end points, although they
can generate safety signals to pursue. The “end of phase 2 meeting” can be
an important early point in the lifecycle of the drug to identify and track
potential safety issues and to ensure that the sponsor’s protocols address
key questions.
Roles of the Office of New Drugs and the Office of Drug Safety/Office of
Surveillance and Epidemiology Premarket Period
OND is responsible for premarket reviews, makes approval decisions,

and retains authority for regulatory decisions after a drug is marketed. OND
clinical reviewers typically are physicians, some with epidemiology training,
who are skilled in review of clinical trials. DDRE staff are mostly phar-
macists and epidemiologists whose expertise tends to be in observational
studies and whose primary focus has been on monitoring and evaluating
postmarket data. Traditionally, the OND review team has drawn on ODS/
OSE, and particularly DDRE, as safety consultants when they determined
a need for a specific safety review.
DDRE staff routinely participate in a limited number of premarket ac-
tivities; they have historically functioned in a consultation capacity to OND,
called on to perform specific safety reviews. In a recent report on postmar-
keting drug safety, the Government Accountability Office characterized
ODS/OSE as a consultant to OND in the postmarket period and described
a problematic working relationship between the two offices (GAO, 2006).
In its official response to that report, FDA asserted that the “consultant”
term understates the importance of ODS/OSE and referred to the agency’s
efforts to “foster a partnership” between ODS/OSE and OND that makes
them equals in the postmarket identification and timely resolution of drug
safety issues (GAO, 2006). FDA’s recent efforts to integrate the work of
the two offices better may also extend to the premarket period. Chapter 3
discusses the challenges in the OND and ODS/OSE relationship and recent
efforts to address them.
One of the 17 drug-evaluation divisions (see organization chart), the
Division of Neurology Products (DNP), has a safety team in the unit. The
DNP and the Division of Psychiatry Products were combined in the past and were separated
in the 2005 reorganization of OND. They both continue to use the safety team, which now
officially reports to DNP.

safety team’s role is to quantify and set priorities among potential risks
posed by the drug they are reviewing. They do not make recommendations
on a drug’s approvability (Racoosin, 2006). The committee was told that
discussions have occurred in FDA about including a full-time safety officer
in the other ODS/ODE divisions. Two possible explanations for why that
has not occurred were offered: shortage of safety officers and the fact that
some divisions do not review enough applications to support a full-time
safety officer.
Completion of Clinical Trials and Their Limitations
Clinical trials typically take 2–10 years to complete (PhRMA, 2006),

depending on such factors as the rate of the event of primary interest, the
length of patient followup, the staging of trials, and the difficulty of accruing
patients. When data from phase 2 trials seem extremely promising, particu-
larly in the context of serious or life-threatening diseases or conditions, an
NDA may be filed without proceeding to or completing phase 3 trials. For
example, azidothymidine (AZT) was approved for treatment of HIV infec-
tion on the basis of phase 2 trials (Grassley et al., 2004).
Only about 20 percent of drugs that enter phase 1 trials go on to be
approved and marketed (lower estimates have been provided by others so
the true percent is unknown) (DiMasi et al., 2003; PhRMA, 2006). A spon-
sor may decide to halt trials for various scientific or commercial reasons.
A recent study found that the number of clinical trials being conducted in
the United States leveled off in 2000 and then started to decline in 2002.
The author attributes the decline to cancellation of late-stage trials (Kaitin,
2005).
Even when a sponsor completes its trials and submits the resulting
data in support of an NDA, important safety information about the drug is
not yet available. That point is essential for an understanding of the drug
regulatory system and the incomplete safety profiles of the drugs that enter
the marketplace.
The gaps in critical information, such as safety data, are due to a num-
ber of factors, including the limited number of subjects studied and the ways
in which the subjects and the research setting differ from the conditions of
use when the drug is marketed (CDER et al., 1998). Preapproval trials typi-
cally are too small to detect even significant safety problems if they are rare.
An adverse event (even a serious one) that occurs in less than one in 1,000
patients cannot be reliably detected except in the largest premarket trials
but can pose a serious public health problem when hundreds of thousands
FDA may grant accelerated approval on the basis of surrogate endpoints, but approval is
conditional on sponsors’ undertaking or completing validation trials.

or millions of people use the drug (GAO, 1990; Okie, 2005; Racoosin,
2006). For example, bromfenac, a non-steroidal anti-inflammatory drug
(NSAID) marketed for 11 months in 1997–1998, was found to have serious
and sometimes fatal liver toxicity in about one in 20,000 people who used
the drug (Friedman et al., 1999); the NDA clinical trial base would have
had to include 60,000 patients to detect such an effect before marketing
(Friedman et al., 1999).
Preapproval clinical trials also have little information on the effects of
long-term exposure to the drug due to their often short duration. Further
more, clinical trials usually do not represent the full array of patients who
will use the product once it is approved. Trials often exclude patients with
comorbidities or those taking other medications, although both may be
common among future users of the marketed drugs. Elderly patients, ethnic
and racial minorities, and the very sick are underrepresented, and pregnant
women are generally excluded from trials. Drugs generally have not been
tested in children as part of the NDA, although patent-extension incentives
are aimed specifically at encouraging pediatric testing in children (Meadows,
2003).
Those limitations are inherent in the system and cannot be changed
without adding considerably to the time and expense of drug approvals,
which would delay patient access to potentially beneficial drugs. It is gener-
ally understood that it is not routinely realistic to require premarket trials on
tens or hundreds of thousands of subjects. Thus, inherent in the fundamental
design of the drug approval system is the delayed availability of important
safety data until a drug is used in larger and more diverse populations after
marketing. That approach means that the initial postmarket period is a criti-
cal time for developing a fuller understanding of a drug’s safety profile.
Premarket clinical trials are designed primarily with efficacy. Safety
issues sometimes surface, but the challenge is the possibility of unusual,
unexpected, undocumented risk. If sponsors and CDER reviewers are not
vigilant about identifying and pursuing safety signals in the trials, the op-
portunity to evaluate safety in the premarket trial period may be lost.
In the premarket period there usually is a shortage of information on
how a new drug compares with other treatments for the same indication.
Sponsors are not routinely required to submit such comparative trials to
obtain approval. Once a drug is on the market, it can be difficult to compel
sponsors or others to undertake appropriate comparative trials. Sponsors
usually do not initiate such trials unless they believe that their product has
a readily identified or demonstrable advantage. A postmarket comparative
trial of newer hypertension agents—angiotensin-converting enzyme (ACE)
inhibitors—against older diuretic drugs, for example, found the older drugs
to be more effective in reducing blood pressure (Appel, 2002). In addition,
comparative trials are expensive, and cost-benefit considerations are not

part of FDA’s statutory purview. (Chapter 4 addresses this topic in greater

detail.) Thus, premarket studies typically do not answer questions of great
concern to health care providers, patients, and payers: Which drug in a class
works work best for most patients? Which is the best first line of treatment?
Which is most cost-effective?
By definition, premarket trials do not address the implications of expan-
sive off-label use, that is, use for conditions in which the given compound
was not studied (or not approved) in tests submitted to FDA (Beck and
Azari, 1998). A recent study found that 21 percent of the 725 million pre-
scriptions written in 2001 were for off-label uses (Boodman, 2006).
Pre-New Drug Application Submission Meeting
As trials are completed and analyzed, the sponsor meets with the review
team to go over the impending NDA submission; it is in the sponsor’s and
FDA’s interest to anticipate issues so that the NDA is complete when sub-
mitted. For example, a 2006 report indicated that when sponsors met with
CDER staff before submitting an NDA, there was a greater likelihood that
the drug was approved on the first cycle (FDA News, 2006b).
According to FDA documents, the discussions include development of
strategies to manage known risks (CDER, 2005b). ODS/OSE staff some-
times participate in the meetings; it may be the first time that ODS/OSE staff
become involved in the IND. (When OND is reviewing a supplemental NDA
for new labeling or manufacturing, ODS/OSE may be active in reviewing
available postmarket data on the approved indication.)
NEW DRUG APPLICATION

In the last couple of years, FDA has received 110–120 NDAs per year
(FDA and CDER, 2005). The average size is 235 MB with 250 files, the
equivalent of almost 400 volumes of 500 pages each, or about 200,000
pages (Henderson, 2006). Often, an NDA does not arrive all at once—FDA
allows gradual submission for fast track studies (rolling review). Sponsors
are also required to provide additional data that become available during
the review process.
Data management is a critical task with a project of this size. Scientific
reviewers need sophisticated knowledge of and access to programs for
managing and analyzing the data. In addition, because sponsors have some
“Fast track is a process designed to facilitate the development, and expedite the review of
drugs to treat serious diseases and fill an unmet medical need. The purpose is to get important
new drugs to the patient earlier. Fast Track addresses a broad range of serious diseases” (FDA,
2006c).

leeway in how they present their summary safety and efficacy data and
where in this massive file they are found, reviewers must sometimes devote
considerable time to finding the critical safety data needed for the review.
ODS/OSE involvement is typically limited to meeting attendance and pro-
viding consults at this point in the process. The arrival of data on a rolling
basis can further complicate the process. Sponsors can submit materials
to the NDA fewer than two dozen times, as was the case with cinacalcet
hydrochloride (Meyer, 2004), or as many as 70 (or even more) times, as
occurred with sibutramine (Bilstad, 1997).
Prescription Drug User Fee Act Timetables and Performance Goals

Triggered
When FDA receives the final piece of an NDA the Prescription Drug
User Fee Act (PDUFA) clock begins ticking (FDA, 2005f). PDUFA was en-
acted in 1992 and reauthorized in 1997 (PDUFA II) and 2002 (PDUFA III).
It is up for reauthorization in 2007. The law provides for the pharmaceutical
industry to pay user fees to FDA to be used primarily to staff and resource
new drug (and biologic) review divisions, in exchange for which FDA agrees
to expedite drug reviews according to specific timetables. PDUFA has also
established deadlines to expedite the premarket review process, to schedule
meetings requested by industry, resolve disputes, to respond to questions
about study protocols, and develop guidances (see Box 2-2 and Appendix C
for the goals, and see Chapter 3 for additional discussion of PDUFA).
The PDUFA II and III goals call on FDA to review and act on 90 per-
cent of standard original NDAs within 10 months and 90 percent of prior-
ity NDAs in 6 months. A priority NDA review is intended for drugs that
“represent significant improvements compared with marketed products”
(FDA and CDER, 2005). PDUFA has resulted in a dramatic decline in new
drug review time. For standard NDA reviews, the median FDA review time
was 11.9 months in 2004, down from 20.8 months in 1993 (FDA, 2005d;
CDER, 2006). For priority NDA reviews, the median review time was 6.0
months in 2004, down from 16.3 months in 1993 (Weiss Smith, 2006).
Initial Filing Review
CDER does an initial review of an NDA to determine whether it is ac-

ceptable for review. Within 60 days, CDER informs the sponsor if there are
Sponsor submitted data to FDA 19 times from September 8, 2003, through March 5,
2004.
Sponsor submitted data to FDA 85 times from August 7, 1995, through November 22,
1997.

substantive deficiencies in the file that cause FDA to “refuse to file” the ap-
plication (CDER et al., 1998). That occurs when the NDA has such critical
deficiencies that it clearly is not approvable as submitted. When submitted,
the NDA is also designated as a standard (10-month timetable) or priority
(6-month timetable) review by the division office or office director. A minor-
ity of NDAs have been designated as priority reviews. In 2004, for example,
29 of the 119 NDAs submitted were priority reviews, and the remaining
90 were standard reviews. Most priority reviews involve new molecular
entities (NMEs). An NME is defined as “a medication containing an active
substance that has never before been approved for marketing in any form in
the United States” (FDA and CDER, 2001b). Of the 119 NDAs submitted
in 2004, 36 were for NMEs, and 21 of these were assigned priority status.
(See Table 2-1 for past NME priority and standard approval numbers.)
Assembly of Review Team and Beginning of Review
Within about 2 weeks of receiving an NDA, CDER names a review

project manager and primary scientific reviewers. Although reviewers who
were involved with the IND are strong candidates for the review, the team
does not necessarily include all those involved earlier. Some members of
the original team may be too busy with other work, may have moved on to
other positions, or may have left FDA.
Reviewers’ workloads typically include premarket reviews and supple-
mental NDA reviews and issues arising with marketed drugs that they previ-
ously reviewed. They may also be involved in writing guidance documents or
may be participating in other CDER or FDA initiatives; in the wake of highly
publicized concerns about safety, CDER has launched a number of initiatives
in the last year to evaluate, articulate, and improve procedures. Obstacles in
hiring new staff due to a change in Department of Health and Human Services
human resources policies have placed added strain on the workforce.
The review team includes OND staff with expertise in various medical
and scientific specialties—including clinical medicine, pharmacology, and
toxicology—and CDER reviewers from outside OND with expertise in such
fields as chemistry, manufacturing and controls, microbiology, and statistics.
In some cases, outside experts (special government employees) may partici-
pate in reviews (CDER et al., 1998; FDA, 2006c).
In consultation with the clinical team leader and perhaps other team
members, the primary clinical reviewer will ultimately be responsible for
There are inconsistencies in CDER documents in the use of medical review or clinical review.
They appear to be interchangeable terms. It has been suggested that use of clinical review indi-
cates that a primary reviewer need not necessarily be a physician, although most of them are.
In this report, we will use the more inclusive term clinical review or clinical reviewer.

BOX 2-2
Select PDUFA Goals
Clinical Development
Under PDUFA, FDA’s goal is to reply to a sponsor’s complete response to a
clinical hold within 30 days of the agency’s receipt of the submission of such
sponsor response, and do this for at least 90% of such submissions. Rapid
resolution of safety issues that lead to clinical hold helps ensure patient safety
while enabling access to the experimental treatment.
FDA Oversight and Review of Clinical Trial Protocols During

Development
Under PDUFA, FDA will evaluate specific questions about the sponsor’s spe-
cial study protocol designs for carcinogenicity, stability and phase 3 for clinical
trials that will form the primary basis of an efficacy claim.
• FDA will review scientific and regulatory requirements for which the
sponsor seeks agreement.
• FDA’s goal is to provide a succinct written response, within 45 days of
receipt of the protocol and specific questions, and do this for at least
90% of such submissions.
Sponsor-Requested Meetings with FDA During Clinical Development

Under PDUFA FDA’s goal is to review all filed original NDA/biologics license
application (BLA) submissions within the following time frames:
TABLE 2-1 Numbers of Priority and Standard

NME and New BLA Approvals, 1995–2004
Year Priority Standard Total
1995 10 19 29
1996 18 35 53
1997 9 30 39
1998 16 14 30
1999 19 16 35
2000 9 18 27
2001 7 17 24
2002 7 10 17
2003 9 12 21
2004* 21 15 36
2005* 15 5 20
*Includes BLAs for therapeutic biologics.
SOURCE: Adapted from the 2004 and 2005 CDER Report
to the Nation.

• Review and act on 90% of priority applications within 6 months.

• Review and act on 90% of standard applications within 10 months.
For all NDA/BLA resubmissions:
• Review and act on 90% of Class 1 resubmissions within 2 months.
FDA Filing and Review of Submitted Marketing Applications

(NDA/BLA)
Under PDUFA FDA’s goal is to review all filed original NDA/BLA submissions
within the following time frames:
• Review and act on 90% of priority applications within 6 months.
• Review and act on 90% of standard applications within 10 months.
For all NDA/BLA resubmissions:
Under PDUFA FDA’s goal is to review all filed original Efficacy Supplements
within the following timeframes:
• Review and act on 90% of priority efficacy supplements within 6
months.
• Review and act on 90% of standard efficacy supplements within 10
months.
preparing and signing the written review of the NDA. The primary review
summarizes and analyzes the clinical data in the NDA and provides the
reviewer’s assessment and conclusions regarding the effectiveness and safety
data. It also sets out the reviewer’s assessment of the proposed directions
for use and includes a recommendation for regulatory action. The other sci-
entific reviewers will each write and sign “discipline reviews” that evaluate
the NDA from the point of view of their expertise, and the primary review
includes a summary of those reviews. The team leader will sign off on the
primary review, sometimes adding a memo that summarizes broader issues
or professional disagreements raised by the NDA (CDER, 2004).
If the NDA is for an NME—that is, an active substance that has not been
approved before—the OND office director or deputy director must sign off
on the approval. When it is not for an NME, the director or deputy director
of the review division in OND can sign off on the approval decision.

The NDA contains data from animal and human studies; it is illegal to
exclude any pertinent data. It also has information on product manufac-
turing and characteristics, packaging and labeling for both physician and
consumer, IND data, and the results of any additional toxicologic studies
that were not included in the IND (21 CFR 314.50) (CDER et al., 1998).
Data on the use of the drug outside the United States may be included in
the NDA. In the early 1980s, only about 2 or 3 percent of new drugs were
first marketed in the United States, so useful safety data on use abroad could
sometimes be included (Friedman et al., 1999). By 1998, that proportion
grew to 50 percent and the proportion of drugs launched in the United States
first has increased with each reauthorization of PDUFA: I, 25.23 percent; II,
47.19 percent; and III, 50 percent (FDA, 2005d; Okie, 2005).
Unlike their European counterparts who generally rely on the sponsor’s
summaries, FDA reviewers compile and reanalyze the data submitted by
the sponsor and use the analyses, as well as the one done by the sponsor, to
inform their decision about the drug.
Throughout the review process, the sponsor may be submitting amend-
ments in response to FDA requests or to complete work identified in the
pre-NDA meeting. If major amendments arrive in the last 3 months of
the review, the PDUFA clock may be extended (FDA, 2002). As issues
arise, the sponsor or FDA may request formal meetings during the process
to resolve disputes or discuss pending concerns. The number of such meet-
ings varies, but it is not uncommon for several meetings to be held while
the application is under review.
PDUFA establishes specific timelines for FDA to respond to an indus-
try request for a meeting, schedule the meeting, and distribute minutes
from it (FDA, 2005g). The PDUFA goals were associated with about a 33
percent increase in sponsor-requested meetings from fiscal year (FY) 1999
to FY 2004 (FDA, 2005d). That has required FDA staff to devote many
hours to planning, conducting, and following up on the meetings. Although
time-consuming and resource-intensive, the meetings can clarify issues and
improve the review process by reducing the risk of misunderstandings late
in the review process.
Advisory Committees
During the review process, a decision may be made, usually by the divi-
sion director, to convene an advisory committee meeting (see Box 2-3 for
deadlines to convene an advisory committee meeting). Advisory committees
are used as a source of independent advice from experts outside FDA (FDA,
2006b). Chapter 4 discusses advisory committees in more detail.

BOX 2-3
Timeline for Planning an Advisory Committee Meeting
Planning of an advisory committee meeting takes roughly 4 months and
involves the following:
• Advisory committee members must fill out a “Conflict of Interest

Disclosure Report for SGEs” (form 3410) for each topic to be
discussed.
• FDA staff (advisory committee oversight and management) must
determine whether existing advisory committee members have
a conflict of interest (COI) regarding the current topic and what
other expertise they need (if not already on the committee, or to
replace a committee member with a COI in that topic).
• Five weeks before the meeting: proposed waivers need to be
submitted for approval. Waivers are reviewed by
– committee members
– the executive secretary
– the committee management specialist
– the program officer
– the chief of scientific advisers and consultants staff
– the ethics specialist
– the director of advisory committee oversight
– the senior associate commissioner.
• The dockets office needs a few days to a week to prepare the
posting for the Federal Register.
• Fifteen days before the meeting: FDA must post notice of the
advisory committee meeting, including the topic to be discussed
and any waivers obtained for the meeting on its Web site (Hinchey
Amendment). FDA also posts this information in the Federal
Register.
• No later than the day of the meeting: if the Secretary of Health
and Human Services or FDA discovers a COI less than 15 days
before the advisory committee meeting, the agency must make a
disclosure as soon as possible but in any event no later than the
date of the meeting (Hinchey Amendment).
CDER has 17 topic-specific advisory committees, each composed

mainly of clinical experts in a specific field, such as gastrointestinal or onco-
Number of advisory committees in other units of FDA: Center for Biologics Evaluation and
Research = 5, Center for Devices and Radiological = 21, Center for Food Safety and Applied
Nutrition = 1, Center for Veterinary Medicine = 1, National Center for Toxicological Research
= 2, Office of the Commissioner = 2.

logic drugs (FDA, 2006a). Advisory committees roughly match the medical
specialties of the review divisions in OND. In addition, the Drug Safety and
Risk Management Advisory Committee provides guidance on issues related
to safety and research methods (CDER, 2005a).
Typically, advisory committees are convened when applications involve
new or complex technologies or to address controversies (FDA, 2006b).
Sometimes, they are used to address general concerns not related to the ap-
proval of a specific product, such as the acceptability of a particular study
design or the use of a particular endpoint as a surrogate (FDA, 2006b).
Committees convened to assess an NDA may be asked to comment on
whether the data support product approval; on some unique aspect of safety,
effectiveness, or clinical development of the product; on whether additional
studies are needed; or on whether changes should be made in a drug’s label
or other action should be taken in response to new risk information after
a drug is approved.
After presentations by the sponsor and agency representatives and a
public comment period, the committee members usually vote on the ques-
tions posed to them by FDA staff. The votes are not binding (FDA, 2006b),
but FDA decisions usually are consistent with the majority vote. The meet-
ings can lead FDA to request additional information from the sponsors.
Safety Tracking
As described in Chapter 1, FDA has been under pressure to speed drug

reviews and get promising therapies to patients sooner (Lurie et al., 1999)
for at least two decades. PDUFA established goals for speed that, as noted,
have resulted in substantial decreases in review time. However, no compa-
rable safety goals drive the review process. Case studies of specific drugs
point out both the strengths and the weaknesses of FDA’s investigation of
safety signals in specific instances, but there seems to be no overall metric
in place comparable with measures of speed to track how safety is being
monitored and assessed.
Individual drug evaluation offices in OND seem to differ in how and
the extent to which they track safety issues regarding drugs that they are
reviewing. The committee has been told that for the last 2–3 years OND’s
senior leadership has listed and tracked safety issues by office at its weekly
meetings (IOM Staff Notes, 2005–2006). Difficult or controversial safety
issues are sometimes discussed at “regulatory briefings,” which are attended
by staff from various parts of CDER and allow wider input on important
questions faced by individual divisions, promote consistency in approach
and decision-making, and raise awareness of emerging issues throughout
CDER.
In response to congressional and public concerns, CDER has expanded

its safety-oversight infrastructure over the last 2 years. In 2006, a new

position of associate center director for safety policy and communica-
tions was created in CDER with responsibility for overseeing safety issues
(FDA, 2006c). In early 2005, the Drug Safety Oversight Board was created
to increase both oversight and transparency in matters of safety (CDER,
2005c). It is too early to know whether those highly publicized initiatives
will strengthen oversight of and communication about safety.
Dispute Resolution
Differences of opinion among reviewers may surface at various points

during the review process or in the postmarket period. Sometimes, they re-
flect different professional perspectives on how to assess and weigh the types
of data available and draw a conclusion. The evaluation of drugs is a team
process, incorporating experts in a wide array of disciplines who must work
together effectively. Furthermore, reviewers rarely have all the information
they would like to have to make the required scientific determinations; in
this environment of scientific uncertainty, legitimate differences of opinion
on the appropriate course of action are inevitable. But a regulatory decision
must be reached and must incorporate the most persuasive and compelling
scientific assessments, while leaving all participants feeling that they have
been heard.
Disparate views may be discussed at global assessment meetings when
the whole review team tracks the review in progress or in other informal
or official meetings. Where disagreement persists, upper-level supervisors
have traditionally had responsibility for evaluating the options and making
a decision to resolve the disagreement.
In a few high-profile cases, internal disagreements about CDER’s han-
dling of safety issues on particular drugs or in general have been aired in
the mass media or in congressional hearings (Graham, 2004; Hensley et al.,
2005; Neergaard, 2005). Surveys of CDER staff reveal some concern about
decision-making regarding postmarketing safety (DHHS/OIG, 2003). (See
Chapter 3 for more information on this topic.)
In November 2004, CDER created a pilot program in the CDER
ombudsman’s office to provide a forum to discuss and resolve differences
(MAPP 4151.210). It provides for dispute resolution at the center direc-
10This MAPP provides a new pilot procedure for CDER staff to express their differing pro-
fessional opinions (DPOs) concerning regulatory actions or policy decisions with substantial
public health implications in instances when the normal procedures for resolving internal dis-
putes are not sufficient. The DPO procedure provides short timeframes for hearing a differing
professional opinion so that it can be resolved expeditiously, review of the DPO by qualified
staff not directly involved in the decisions, and evaluation of the pilot after 1 year to determine
whether it adds value to the regulatory decision-making process.

tor level. No CDER employees have used the program as of early 2006,
however.
The inclination of senior management at CDER to intervene at earlier
stages when disputes occur in CDER may be a function of management style
and the existence of processes that make them aware of developing issues, as
well as competing demands on their time. Senior managers are responsible
to constituencies both in CDER and outside CDER, such as the Office of
the Commissioner and Congress.
Key Review Meetings
Reviewers, consultants, and supervisors interact throughout the review

process, but the midcycle review at the end of the 5th month for standard or
the 2nd month for priority drugs is a prescribed time to make a more formal
assessment of findings and to raise questions about the application.
Later, the results of the various review activities are integrated during an
internal “wrap-up” meeting that begins the “action phase” of the NDA. The
meeting is intended to occur by the end of month 8 for standard or month
5 for priority drugs, by which time the team should have a comprehensive
understanding of the safety, efficacy, and quality of the drug under review
(CDER et al., 1998, 2005). An FDA guidance document states that a pre-
liminary decision is made on the regulatory action at the meeting (CDER
et al., 2005). Critical elements—such as risk management, major labeling
issues, and postmarket commitments—are considered. If PDUFA deadlines
are to be met, actions must be developed expeditiously and, as noted below,
plans can sometimes be developed hurriedly.
The preapproval safety conference, held near the time of approval, is a
key meeting in the safety review process. It is a time for the team to review
the NDA safety base comprehensively and explore safety issues that could
warrant careful monitoring after approval. Discussions may lead the regula-
tors to ask the sponsor to conduct additional safety studies either before or
after approval. ODS/OSE staff are typically involved in this meeting.
Risk Minimization Plans
Some approval plans for NDAs include risk minimization action plans
(RiskMAPs), strategic plans developed by the sponsor to minimize known
risks posed by a product while preserving its benefits (DHHS et al., 2005).
They go beyond the requirements for all sponsors to minimize risks through
such efforts as accurate labeling and adverse event reporting. RiskMAPs ap-
ply primarily to products that “may pose a clinically important and unusual
type or level of risk” (DHHS et al., 2005). PDUFA (III) requires ODS/OSE
to be involved in reviewing RiskMAPs.

As part of PDUFA (III), OND and ODS/OSE (and FDA’s Center for
Biologics) developed guidance documents for industry on how to develop
RiskMAPS to assess, manage, and monitor known risks posed by a product
(both before and after approval). In its guidance (FDA, 2005b), FDA notes
that risk management (defined as risk assessment and minimization) is an
iterative process and sets out four steps: (1) assessing a product’s benefit/risk
balance, (2) developing and implementing tools to minimize the risks associ-
ated with it while preserving its benefits, (3) evaluating the effectiveness of
the tools and reassessing the benefit-risk balance, and (4) making appropri-
ate adjustments to the risk minimization tools to improve the benefit-risk
balance further. FDA calls for those four steps to be ongoing throughout
a product’s lifecycle, with the results of risk assessment informing the
sponsor’s decisions regarding risk minimization (FDA, 2005b).
RiskMAPS are relatively new and still a work in progress. CDER staff
have challenging scientific, policy, and resource issues to work out, both in
general and for specific drugs or classes of drugs.
Postapproval Requirements and Labeling
The final days of NDA review typically involve negotiations between

the sponsor and the regulators about the drug label and postmarket require-
ments. It is the sponsor’s responsibility to develop a study protocol when
it is agreed that a postmarket study will be undertaken and to draft label
language; it is CDER’s job to provide input and review and to comment on
the sponsor’s plans or suggested product labels.
CDER usually seeks commitments from sponsors to undertake postmar-
ket (phase 4) trials or other studies to define risks further in some popula-
tions or under some conditions of use. Despite their importance, discussion
of such studies is often delayed until late in the review process, when little
time is available to consider the specifics of the protocol. With FDA facing
a PDUFA deadline and with approval at stake for the sponsor, agreement is
sometimes reached on studies that later prove to be infeasible or unjustified
for a variety of reasons. It may be because ethical concerns preclude ob-
taining IRB approval or because of inability to recruit study subjects. Study
designs may also be superseded by new treatments or findings that would
undermine the value of a trial.
FDA may ask sponsors to take other actions, such as establishing a
registry of patients who are taking the drug. An example is pregnancy
registries, which are surveillance studies in which women who take a
particular medication or have a particular condition during pregnancy
answer questions before and after childbirth. There are eight registries for
specific medical conditions (while taking a certain class of drugs to treat
that condition), such as asthma and epilepsy (as of July 2004) and 14 for

specific medicines (as of July 2003) (Kennedy et al., 2004; FDA and Office
of Women’s Health, 2006).
Negotiations about the wording of a drug label also come late in the
process, when all the information about the drug has been pulled together.
The label specifies conditions of safe use of the drug (CDER et al., 1998).
It is the official description of a drug product and includes the drug’s indi-
cation; who should take it; adverse effects; special instructions for use of
the drug in pregnant women, children, and other populations; and safety
information for the patient. Although FDA can refuse to approve a drug if
the sponsor fails to agree to what the regulators want in the label, the final
label is typically a result of negotiations between regulators and sponsor.
In the case of serious safety concerns, FDA may direct the sponsor to
highlight a safety warning in the label by putting a black box around it.
These may be added to marketed drugs when new data become available.
A recent example are antidepressant medications, which now require a
black box warning describing the risk and emphasizing the need for close
monitoring of suicidality of patients (FDA News, 2004).
Although the product labeling is intended to guide prescribers in use of
a drug, studies show that prescribers often fail to follow the label (Public
Health Newswire, 2006). For example, cisapride was contraindicated in pa-
tients at increased risk for cardiac arrhythmias, but 20 percent of its use was
in such patients (Ray and Stein, 2006). The label for troglitazone specified
that liver-function tests were required, but often they were not performed
(Ray and Stein, 2006).
Some approved drugs (such as cisapride) have a narrow therapeutic
index; that is, the toxic dose is close to the effective dose so that there is a
small margin of error for triggering safety problems. Such drugs make it
incumbent on the sponsor and FDA to develop careful risk management
strategies and incumbent on practitioners to be cognizant of proper use.
The Institute of Medicine report Preventing Medication Errors discusses
matters related to patient comprehension of and adherence to medication
labeling (IOM, 2007). In an effort to improve awareness of labeling direc-
tions, FDA in January 2006 announced a revision of the label format (FDA
News, 2006a) (see Appendix A for more detail).
FDA requires sponsors to provide patient medication guides (known as
MedGuides) for drugs with “special risk management information” (FDA
and CDER, 2006a). There are 42 medications marketed by brand name
and 38 by active ingredient that have MedGuides that must accompany
them when they are dispensed (Wolfe and Public Citizen’s Health Research
Group, 2005; CDER, 2006) (see Chapter 6 for additional discussion).
FDA has imposed restrictions on the distribution of some new drugs
(such as drugs containing isotretinoin) which are discussed in Chapter 4.
But there appears to be a lack of clarity about the scope of FDA’s authority

under the Food, Drug, and Cosmetic (FD&C) Act to restrict distribution.
General counsels to FDA have apparently differed in their interpretation of
the FD&C Act in that regard over the last decade. The statute governing
medical-device regulation, which was enacted more recently than the FD&C
Act, is more explicit about FDA’s authority to restrict product distribution
to protect the public health.
Site Inspections
Before an NDA can be approved, FDA usually inspects the facilities

and manufacturing processes that will be involved in producing the prod-
uct (FDA, 2006c). That process usually occurs toward the end of the NDA
process and it is likely that the records of at least some of the clinical trial
investigators will be inspected (Huddleston, 1999). Often sponsors continue
to refine their manufacturing processes after the product is approved; those
changes must approved by FDA. In FY 2004, 1,610 chemical and manufac-
turing control supplements were submitted.
Letter Sent to Sponsor
FDA may send the sponsor a “not approvable” letter that explains
why an application cannot be approved on the basis of current informa-
tion, an “approvable” letter stating that the product could be approved if
specified additional actions were taken, or an “approval” letter indicating
that the product has been approved with specified labeling and postmarket
requirements (21 CFR 314.100a [2001]). The review team participates in
the drafting of the letter, and it is signed by the division director or office
director, depending on the product. (See Box 2-4 for a list of NDA review
elements.)
POSTMARKET PERIOD
Historically, drugs undergoing premarket review have received more
attention in and outside FDA than drugs that are in the marketplace. There
is now growing awareness that a robust drug safety system requires a life-
cycle approach (Crawford, 2005) and that drug approval triggers a critical
period for monitoring safety. The budget for postmarketing surveillance and
assessment is not commensurate with FDA’s growing scope.
DDRE in ODS/OSE monitors marketed drugs and prepares safety
reviews and risk assessments. Although ODS/OSE staff may contribute to
the development of risk management plans, it is OND that has responsibility
for deciding what regulatory action to take in response to new safety infor-
mation. ODS/OSE has undergone enormous change in the last decade, with

BOX 2-4
Current Review Elements for New Drug Approval
• Periodic team progress check-ins
• Midcycle review meeting
• Team or subgroup interaction on particular issues
• Primary review completion
• Secondary (team leader or branch chief) review
• Review division director, or higher level, review
• Consult review input
• Advisory committee meetings
• Internal briefings for signatory authority
• Wrap-up (integration of review, consult, and inspection input)
• Preapproval safety conference (CDER)
• Preapproval facility inspections (BLAs)
• Labeling negotiation
• Issuance of action letter by PDUFA goal date
numerous leaders and acting leaders, name changes, and reorganizations

(GAO, 2006). In recent years, it has also assumed expanded responsibilities,
and its pharmacists and safety officers are monitoring more products and
conducting more assessments, relying on the array of data sources and tech-
nologies described below (FDA and CDER, 2005) (see Chapters 3 and 4 for
additional discussion of ODS/OSE and OND functions and relationship).
Drug Promotion and Information
The Division of Drug Marketing and Communication (DDMAC) in

ODS/OSE is charged with reviewing sponsor promotional materials. The
DDMAC staff of 35 reviews more than 53,000 promotional pieces every
year, including print and broadcast direct-to-consumer (DTC) advertising
(see Chapter 5 for detailed discussion) and materials prepared for profes-
sional conferences and for health care providers. FDA does not have the
authority to review or sanction promotional material before launch or
release (or to review instructions given by sponsors to their sales force) un-
less they are voluntarily submitted by the sponsor; it often reviews material
after it has been released or broadcast, and it can then require corrective
action in letters sent to the sponsor. However, many sponsors submit their
promotional material in advance to ensure that they will not encounter
regulatory problems later.

Since 1997, when FDA eased rules for DTC advertising, companies have
greatly expanded their use of it to promote drugs via the mass media (Gahart
et al., 2003; Gilhooley, 2005). According to a 2004 study (Brownfield et al.,
2004), the average television viewer spends 100 minutes watching DTC
advertising for every minute in a doctor’s office. Typically, less is known
about the safety of a new drug than of an older drug on the market, but the
public is not likely to be aware of this and may simply assume that a new
drug is a better drug.
Spontaneous Adverse Event Reporting System
The FDA’s primary source for managing and monitoring new adverse
effects of marketed drugs is the Adverse Event Reporting System (AERS),
an automated system for storing and analyzing safety reports. ODS/OSE
has primary responsibility for AERS (FDA, 2004c).
Adverse event reports have several sources. When an adverse event is
both serious11 and unexpected (not listed in the drug product’s current la-
beling), drug sponsors are required to report it to FDA within 15 calendar
days (“15-day reports”). Sponsors must also submit periodic reports that
summarize all adverse events quarterly for the first 3 years after the NDA
was approved and annually over multiple years (FDA, 2005a).
Another source of spontaneous reports is FDA’s voluntary reporting
system, MedWatch, which covers drugs and other FDA-regulated products.
MedWatch enables health care professionals and consumers to file adverse
event reports directly to FDA via telephone, completion of FDA Form 3500
online, or via fax or mail (FDA, 2003).
FDA receives more than 400,000 spontaneous reports each year as part
of the surveillance system. In FY 2004, for example, ODS/OSE received
422,889 adverse event reports (see Box 2-5 for a breakdown) (FDA and
CDER, 2005). Although exact figures are not available, that is assumed
to represent a small fraction of all adverse effects of drugs. The system
contains 3–4 million reports accumulated from multiple years (FDA and
CDER, 2005).
Most adverse event reports arrive on paper via fax. ODS/OSE has
placed a high priority on increasing the number of reports filed electroni-
cally to both expedite and reduce the cost of receiving and processing the
report. In FY 2004, 16 percent of all reports were submitted electronically,
up from 10 percent in FY 2003 (FDA and CDER, 2005). In the European
11A serious adverse event is any untoward medical occurrence that at any dose: results in
death, is life threatening, requires inpatient hospitalization or prolongs existing hospitalization,
results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect
(CFR 312.32).

BOX 2-5
Adverse Event Reporting in 2004
In 2004, FDA received 422,889 reports of suspected drug-related ad-
verse events:
• 21,493 MedWatch reports directly from individuals (patients or

providers).
• 162,107 manufacturer 15-day (expedited) reports.
• 89,960 serious manufacturer periodic reports.
• 149,329 nonserious manufacturer periodic reports.
SOURCE: FDA and CDER (2005).
Union, where electronic reporting to the European Medicines Agency has

been mandatory since November 2005, over 90 percent of adverse reactions
involving European-authorized medicines have been electronically reported
by manufacturers.
ODS/OSE safety officers are expected to review the “15-day reports”
when they arrive. They continually review incoming reports from Med-
Watch, redirecting those related to other regulated products, and contrac-
tors enter all the MedWatch reports into AERS. Some adverse events (AEs)
from companies, such as those in periodic reports for drugs that have been
approved for more than 3 years or those considered non-serious, are not
are routinely entered into AERS.
The structure of the AERS database complies with a guidance issued
by the International Conference on Harmonisation (ICH E2B). FDA codes
AEs with a standardized international terminology, the Medical Dictionary
for Regulatory Activities (MedDRA). AERS allows for the on-screen review
of reports, the use of searching tools, and various output reports. FDA is
making limited use of data mining software to identify early drug safety
signals in the AERS database via automated searching.
AERS is an important component of the postmarket surveillance system,
particularly for identifying unexpected and rare adverse events (Rodriguez
et al., 2001). For example, aplastic anemia and the rare skin disorder
Stevens-Johnson syndrome have been linked to drugs through AE report-
ing (FDA, 1994). However, AERS is not efficient in distinguishing between
signal and noise from adverse events, such as heart disease, which has a
high background rate in the population (see Chapter 4 for a more com-
prehensive discussion). Some of the limitations of AERS data are the lack

of denominator data on number of users to delineate the frequency of an

event, lack of control groups, recall bias of patients and reporters, poor
case documentation in the reports (critical details that could contribute to
an understanding of an event are missing), and substantial underreporting
of AEs (Ahmad et al., 2005).
Other Postmarket Data
Although AERS data may provide the initial signal of a safety problem,
other studies and databases are typically needed to investigate associations.
Those data include results of clinical trials and epidemiologic studies that
are conducted, or whose results are available, after a drug is approved.
The sponsors’ phase 4 trials are intended to expand the understanding
of the safety and efficacy profile, of selected drugs. However, many of these
studies are not completed (or even begun), for various reasons described
above. FDA lacks the regulatory tools to adequately compel sponsors to
complete appropriate studies (see Chapter 5 for more information). Accord-
ing to a March 2006 report, out of 1,231 agreed-on (by the sponsor) open
postmarket commitments of drugs and biologics, 797 (65 percent) have yet
to be started12 (FDA, 2006d).
Another source of postmarket safety data is studies of marketed drugs
designed to investigate new or expanded indications. Sponsors may include
these studies in an efficacy supplement submitted to FDA seeking expanded
label indications. Sometimes these studies may yield important data. For
example, the APPROVe (Adenomatous Polyp Prevention on Vioxx) trial
was designed to identify a new application for rofecoxib and showed an
increased risk of serious cardiovascular events with rofecoxib compared
with placebo—this cardiovascular impact was a secondary consideration
(FDA, 2004b). Post-marketing safety information may also be generated by
sponsors through the establishment of active surveillance systems, such as
pregnancy-exposure registries (Ackermann Shiff et al., 2006).
The National Institutes of Health (NIH) or other agencies may also
sponsor trials to gain new information about marketed drugs. Examples
are the NIH-funded randomized controlled primary prevention trial, the
Women’s Health Initiative, which reported on adverse health effects of
and benefits from use of combined estrogen and progestin (Rossouw et al.,
2002). An earlier NIH-funded study, the cardiac arrhythmia suppression
trial, found that drug treatment for asymptomatic ventricular arrhythmia in
patients who had a heart attack did not prevent—and in fact substantially
increased the risk of—sudden cardiac death. FDA had used a drug’s effect on
12231 (19%) are ongoing; 28 (2%) are delayed; 3 (1%) have been terminated; 172 (14%)
have been submitted.

arrhythmia as a surrogate marker of efficacy, but although the drug reduced

arrhythmia, it also increased cardiac death (NHLBI, 2005).
Additional information on the safety of marketed drugs may come from
large, automated databases. FDA purchases access to some of those data-
bases as a resource for pharmacoepidemiologic studies designed to test hy-
potheses, particularly those arising from AERS. (Chapter 4 contains a more
detailed discussion of relevant programs and agreements with academic
research institutions.) FDA also obtains information from IMS Health, a
provider of market research services to the pharmaceutical and health care
industries. Among the services obtained from IMS Health are the National
Disease and Therapeutic Index, which provides data on diagnoses, patients,
and treatment patterns; Integrated Promotional Services, which measures
professional and consumer promotional activity in the pharmaceutical in-
dustry; and the National Prescription Audit, which tracks pharmaceutical
products dispensed in retail, mail-order, and long-term care channels.
Trained staff and (often expensive) supportive technology are typically
needed to use some of those databases fully. CDER’s limited resources for
such activities have precluded taking full advantage of their potential contri-
bution to understanding the safety of approved drugs (see further discussion
in Chapter 4).
Resources also severely constrain their external research program.
DDRE has about 18 epidemiologists. They work with the safety officers
(who are also referred to as safety evaluators and generally are pharmacists)
on assessments, determining for example the background risk of a condition
to determine whether reported rates may be above expected levels. They also
oversee agency-sponsored epidemiologic research.
Identifying and Evaluating Spontaneous Safety Signals
As CDER receives new information related to a drug’s safety profile, it

makes risk assessments and determines how risks can best be managed. For
monitoring purposes, every marketed drug is assigned to a safety evaluator,
usually a pharmacist in DDRE. Generally, one safety evaluator oversees all
drugs in a class, such as statins, so he or she tends to work consistently with
a specific OND division that handles those drugs. AE reports on a drug are
automatically forwarded by e-mail to the appropriate safety evaluator and
to the OND reviewer with responsibility for that drug.
ODS/OSE employs about 25 safety evaluators, and each receives about
500–800 reports a month to monitor, including some that are designated as
“serious” on the basis of criteria established by FDA. The committee was
told that safety evaluators now have less time than before to keep up with
their inboxes as they are spending more time on OND consultations, in
developing complex postmarket risk assessments, and in such activities as

RiskMAP development and assessments required by the Best Pharmaceuti-

cals for Children Act (FDA and CDER, 2005).
Safety officers begin the process of building on initial reports either
when requested by an OND reviewer to pursue a signal or on the basis
of their own review of reports. Initial safety signal information is gener-
ally incomplete or uncertain; for example, a case report has few details,
a patient is taking several drugs at once and a reaction could be related
to the combination or to one of the drugs alone, could be related to the
disease rather than to any of the drugs, or the effect may be so common in
the population that it is difficult to determine whether it is associated with
drug use. Only through additional investigations—including data mining
searching with MedDRA codes, review of premarket studies, and analysis
of available data from sources described above—might a picture begin to
emerge. Increasingly, ODS/OSE is undertaking assessments not just regard-
ing the drug that may have generated reports but regarding the class of
drugs that it belongs to.
Rare is the story that builds as clearly and completely as one would
like for making scientific evaluations and regulatory decisions. Adequate
information to quantify risk or to compare the safety of a drug with the
safety of alternative therapies in its class may not be readily available. Not
uncommonly, uncertainties and professional disagreements about the sig-
nificance of signals persist.
OND and ODS/OSE are expected to work together to assess risk and
determine how to manage it, but OND has authority to make regulatory
decisions related to the findings. A recent Government Accountability Of-
fice report noted problems in the relationship between ODS/OSE and OND
staff, including lack of clarity about roles and responsibilities and commu-
nication barriers (GAO, 2006). As noted earlier, FDA’s official response to
those findings cited its commitment to making ODS/OSE and OND “co-
equal partners in the post-market identification and timely resolution of
drug safety issues” (GAO, 2006) (see discussion in Chapter 3).
Another challenge facing FDA is to decide when to alert the public and
providers of AE reports that are under investigation. On one hand, report-
ing at the earliest stages could confuse and perhaps unduly alarm patients
and providers and lead patients to inappropriately avoid or stop using a
drug that they need. On the other hand, waiting too long to alert provid-
ers and users about potentially serious problems with a marketed drug can
put patients at risk. FDA has been criticized for waiting too long and has
proposed a Drug Watch Web site that would give the public and providers
information about potential problems with marketed drugs earlier than in
the past. The proposed Drug Watch program has been subject to criticism
from the pharmaceutical industry. One reason given by industry against the
program is that it is not useful to look at one study in isolation, as would be

the case in Med Watch; they would prefer that similar studies be published
together giving physicians and patients the opportunity to see the data in
context (Agres, 2006). This has prompted FDA to rethink the program, so
launch of that program has been delayed (FDA, 2005c,e).
To help to resolve uncertainties, discuss issues publicly, or consider
regulatory strategies to address a risk, an advisory committee meeting may
be held. Members of the Drug Safety and Risk Management Advisory Com-
mittee and the committee with expertise in the specific class of drugs are
typically involved.
Regulatory Actions
FDA’s regulatory authority is grounded in the FD&C Act and its

amendments (21 USC 301). The historical origins of the act lie in the many
19th- and 20th-century incidents of widespread injury caused by ingestion
of items that were either tainted versions of otherwise safe substances or
unsafe substances marketed as something else entirely.
Fundamentally FDA’s authority is limited to prohibiting the marketing
of a drug that is adulterated or misbranded. With the middle-20th-century
amendments came an expansion of the notion of misbranding, in which
any failure to prove efficacy and safety before marketing would result in
a finding of misbranding, because the marketing of the product would be
a form of deception. Similarly, failure to adhere to agreed-on labeling or
advertising requirements was viewed as a form of misbranding. The result
is that FDA’s remedies for the marketing of dangerous or mislabeled drugs
is limited largely to withdrawing them from the market. The threat of such
an action (although for critical or popular therapies such a threat may not
be credible) and the agency’s ability to use the mass media to call attention
to the controversy give the agency some teeth in getting sponsors to comply
with regulatory actions. Actions may include mandatory postmarketing
surveillance, limitations on distribution, special education programs, or
labeling changes, including use of a black box warning to call attention to
serious risks. FDA also uses “Dear Health Practitioner” letters to inform
providers of new information related to the safe and effective use of a mar-
keted drug.
Such actions have been taken numerous times although enforcement
activities have varied over the years. Decisions about use of enforcement
tools, especially such aggressive ones as seizing products deemed to be mis-
branded, are not CDER’s alone. The general counsel and the commissioner,
both political appointees, are key to those decisions. FDA has come under
criticism from some external stakeholders for not acting quickly enough or
appropriately in the face of serious safety questions in specific cases (Wolfe,
2004; Curran, 2005). Some surveys also indicate concerns among CDER

staff respondents about how safety issues are handled (DHHS/OIG, 2003)
although senior management has strongly defended controversial actions
(IOM Staff Notes, 2005–2006). FDA does not routinely conduct “postmor-
tems” of drug withdrawals as a basis for examining and possibly improving
its procedures. Drugs withdrawn from the market have been reinstated by
FDA for use with restrictions at the request of the sponsor (see Box 2-6 for
summary of this case).
One important issue for FDA and all other stakeholders in drug safety
is the limited effectiveness of these regulatory warning tools in promoting
drug safety. Although changes in the information provided in a label is a key
tool for responding to and communicating new safety information, studies
show that many patients are at risk because providers and the patients do
not consistently heed labels, including the most serious black box warnings
(Lasser et al., 2006).
It is worth underscoring that the fundamental design of the drug ap-
proval system described above—separate from the quality of the data that
sponsors generate in compliance with it—inevitably puts drugs on the mar-
ket when safety information is incomplete. The obvious corollary is that the
postmarket monitoring system, as well as the premarket review processes,
must be as effective and efficient as possible.
BOX 2-6
The Story of Alosetron (Lotronex)
November 1999—FDA advisory committee recommends approval
February 2000—FDA approves Alosetron for treatment of “diarrhea-
predominant irritable bowel syndrome” in women
June 2000—FDA advisory committee meeting discusses evidence of
serious adverse events and votes to retain the drug on the
market
November 2000—F DA and the sponsor meet, sponsor withdraws
Alosetron
December 2001—sponsor proposes returning Alosetron to market with
restrictions
April 2002—FDA advisory committee recommends return to market with
restrictions
June 2002—FDA approves Alosetron’s return to market, with less rigor-
ous restrictions than those recommended by the advisory
committee
SOURCE: Moynihan (2002).

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A Culture of Safety
The Committee on the Assessment of the US Drug Safety System has

examined three determinants of organizational culture in the Food and Drug
Administration (FDA) Center for Drug Evaluation and Research (CDER):
the external environment, structural factors, and management. The commit-
tee believes that cultural changes are urgently needed to support a stronger,
more systematic and more credible approach to drug safety in CDER, and
it recommends solutions to problems created or exacerbated by elements
of CDER’s management, structure, and environment. However, implement-
ing some of these recommendations may require additional resources, as
discussed in greater detail in Chapter 7.
ORGANIZATIONAL CHALLENGES
A number of highly publicized events, including the Vioxx withdrawal
and concern about other cox-2 inhibitors, and ongoing drug safety problems
including those related to salmeterol, Ketek, and others have brought FDA’s,
and specifically CDER’s, performance under the scrutiny of the American
public (via the mass media) and Congress (Harris, 2006b; Hendrick, 2006;
Washington Drug Letter, 2006). Critics have charged that there were fail-
ures or delays in informing patients about important drug risks, inadequate
postmarketing assessment of drug safety, and failures to follow up and
enforce sponsors’ postmarketing study commitments agreed on at the time
of approval. Others have expressed concern that the recent focus on safety
could reverse considerable gains in the pace of drug review and the speed
of approving new therapies.
65

Mass media coverage of perceived organizational problems in CDER

has been frequent and detailed, for example, describing an apparent lack
of mutual respect and tension between preapproval review staff and post-
marketing safety staff, and a work environment thought to be marginalizing
dissenting voices on drug safety (Mathews, November 10, 2004; Harris,
February 20, 2005; Henderson, December 6, 2005). As questions about cul-
pability mounted, a series of organizational and programmatic problems in
the center highlighted in the mass media were also examined in government
reports, including the reports of the DHHS Inspector General that surveyed
CDER staff (DHHS/OIG, 2003) and reviewed the state of postmarketing
commitments (DHHS/OIG, 2006), respectively, and the reports of the Gov-
ernment Accountability Office that assessed the impact of the Prescription
Drug User Fee Act (PDUFA) on CDER staff’s morale and workload (GAO,
2002) and examined the structure and effectiveness of CDER postmarket-
ing decision-making processes (GAO, 2006). Many observe signs of an
organizational culture in crisis. It has also become apparent that drug safety
events, whether indicative of or associated with organizational and cultural
problems, have led to diminished agency credibility among the public. Drug
safety experts, members of Congress (including Senators Michael Enzi, Ed-
ward Kennedy, and Charles Grassley, and Representatives Rosa DeLauro
and Maurice Hinchey), consumer organizations (such as Consumers Union,
Public Interest Research Group, the National Consumers League, Public
Citizen), and others have called for organizational, statutory, and resource
changes in the agency. Proposals have included restructuring the agency to
segregate the drug review and postmarketing safety functions by creating
an independent drug safety center (Fontanarosa et al., 2004; Consumers
Union, 2005; Grassley, 2005; Ray and Stein, 2006; Wolfe S, 2006). FDA
itself has undertaken a series of initiatives and changes, described in detail
in Appendix A, including the commissioning of this Institute of Medicine
report (see discussion in Chapter 1) (Crawford, 2004; Wall Street Journal
and Harris Interactive, 2006).
In its discussions with current and recent FDA staff and managers (see
Box 3-1), and on the basis of its review of relevant government reports, the
committee found that the organizational culture in CDER confirms some
of the adverse perceptions conveyed in the mass media, and that the center
is an organization in urgent need of great change.
The committee found that CDER’s organizational culture has both
strengths and weaknesses. The positives are that science-based decision
making is a clear priority that shapes CDER’s culture, as does the staff’s
obvious awareness of the potential consequences of their decisions on the
health of the public and individual patients. The negative features of the cul-
ture include a work environment that is not sufficiently supportive of staff
(as evident in problems with morale and attrition), polarization between

A CULTURE OF SAFETY 67
BOX 3-1
Committee Information Gathering About CDER
Organizational Culture
To inform its deliberations, the committee held information-gathering
sessions to hear from FDA and other stakeholders (see Appendix D).
A small group of committee members and Institute of Medicine (IOM)
project staff visited CDER on October 11, 2005, and February 22, 2006.
From November 7, 2005, to May 2006, IOM staff with rotating committee
representation of one or two members also held confidential discus-
sions with over 30 current FDA staff, including personnel from the Office
of New Drugs (OND) and the Office of Drug Safety (recently renamed
Office of Surveillance and Epidemiology and referred to hereafter as
ODS/OSE), FDA and CDER management, and several former FDA staff
and leaders.*
The committee’s high regard for the professionals who perform CDER’s
preapproval and postapproval functions under considerable time and
resource constraints was reinforced by these conversations. As the com-
mittee gained greater understanding of CDER’s work and functioning,
committee members were able to identify or confirm a number of struc-
tural and related cultural challenges, including a troubling relationship
between OND and ODS/OSE, insufficient management and leadership
to address emerging problems and implement needed reforms, a lack of
clear and consistent processes (for example, for identifying and address
ing drug safety concerns both in the review process and in the post
marketing period, for determining the need for and nature of postmarket-
ing, or phase 4, studies), overextended human and financial resources,
and pressures added by the requirements of the current user-fee funding
mechanism that funds about 50% of CDER’s work (FDA, 2005b).
The major themes that emerged from the committee’s conversations
are consistent with those identified in government reports on FDA and
CDER. The committee also found it helpful to refer to assessments of
organizational problems in other government agencies that deal with risk
and uncertainty, albeit in very different contexts, such as the National
Aeronautics and Space Administration and the Federal Aviation Admin-
istration (GAO, 1996; Return to Flight Task Group, 2005).
*At the committee’s request, the CDER Director sent a letter to all center staff
urging them to contact IOM study staff if they wished to discuss issues related to
their work and recent concerns.

the premarketing and postmarketing review staff, and evidence suggesting

insufficient management attention to scientific disagreement and differences
of opinion.
Change is needed because CDER’s organizational problems may affect
its ability to accomplish the mission of protecting and advancing the public’s
health; they clearly affect public perception of the agency’s performance and
credibility. Every organization has its share of dysfunctions, disgruntled staff
members, and internal disputes, but the committee came away from various
encounters with CDER staff and management with a deep concern about
CDER’s organizational health.
The committee approached this component of its work with special
care, recognizing that structure and culture, as fundamental features of an
organization, connect in complex and not easily discernible ways. Manage-
ment literature shows that an organization’s ability to fulfill its mission is
considerably influenced by the health of its culture, the “social architecture”
that determines whether excellence is promoted; whether the organization
is adaptable, robust, and learning; and whether broad staff participation (in
shaping the vision, making decisions, and so on) is prized and encouraged
(Coffee, 1993; Heifetz and Laurie, 1998; Khademian, 2002). The committee
was explicitly charged with assessing the structure and function of CDER,
but because organizational function is linked to organizational culture, the
committee had to consider CDER’s culture and how it has been shaped
by important changes in the policy, economic, and social environment; by
structural factors, and the related policies and procedures that contribute
to organizational dynamics; and by management. In the pages that follow,
the committee describes the evidence and outlines the steps to be taken to
align CDER’s culture better with its mission “to make certain that safe and
effective drugs are available to the American people.”
The External Environment

Organizational culture is rooted in the external environment, and this is
particularly true of government agencies, which experience the environment
as “a set of constraints, expectations, and pressures” (Khademian, 2002:
136). Some environmental and organizational challenges are peculiar to
government agencies (Claver et al., 1999; O’Leary, 2006; Ostroff, 2006).
For example, their leaders are chosen for attributes that do not necessarily
include a track record of organizational leadership, an ability to transform
complex organizations, or an in-depth knowledge of the leadership is-
sues routinely faced by an agency, and their time in office is usually brief.
Government agency operations are less flexible than those of their private-
Source: http://www.fda.gov/cder/learn/CDERLearn/.

s ector counterparts because of a wide array of laws and regulations and the
requirement that they be responsive to the often conflicting expectations of
multiple constituencies (Ostroff, 2006).
For FDA, and specifically CDER, the environment is shaped by many
factors. First, the evolution of FDA’s regulatory role has been shaped by the
expectations of American society, as expressed through its national legisla-
ture, in its courts, and in the influence of its patient and consumer advocacy
movements. The American public desires timely access to effective and safe
therapies. Legislative attention to the regulation of drugs (and other prod-
ucts in FDA’s purview, has resulted in the statute that dictates FDA’s role: the
Food, Drug, and Cosmetic (FD&C) Act of 1938 and its many subsequent
amendments. Another influence on FDA’s work is the economic and political
agenda of a powerful and influential industry, whose concerns include the
potential of regulation to dampen innovation. The health care delivery sys-
tem (organizations, payors, pharmacies, etc.) and health care professionals
who act as intermediaries between patients and the drug development and
distribution system are another factor in FDA’s environment. Patients must
secure a prescription from a qualified health care provider, and health care
providers can only prescribe drugs that are approved by FDA. FDA actions,
including findings from postmarketing surveillance, inform drug formulary
and reimbursement decisions by payors. Although FDA does not regulate
drug pricing, and cost-effectiveness is not a consideration, these are impor-
tant issues to the health care delivery system, given financial constraints
and the diverse therapeutic needs of its patients. A final crucial dimension
of FDA’s external environment is the potential influence exercised by the
top levels of the executive branch (the White House, the Office of Manage-
ment and Budget) and the legislative branch. Congress plays an oversight
function and provides a forum for the push and pull of legislative factions
concerned with consumer safety and those inclined toward spurring eco-
nomic competitiveness. Congressional concern about the public’s safety may
be one contributing factor to what the industry and other critics have seen
as the agency’s historically risk-averse stance in carrying out its regulatory
duties. In their view, the agency has generally been more likely to err on
the side of greater caution in approving drugs than to err on the side of
faster approval, perhaps in response to the fact that congressional investiga-
tions generally focus on errors of commission (approving an unsafe drug)
rather than omission (not approving a potentially good drug) (Cohn, 2003;
Steenburg, 2006).
The multiple and often conflicting pressures of the external environ-
ment add to the complex nature of the agency’s work (science-based
decision making) and the enormous medical, social, and economic impact
of its regulatory decisions. FDA has a dual mission: to protect public
health “by assuring the safety, efficacy, and security of human . . . drugs”

and to advance public health “by helping to speed innovations that make
medicines . . . more effective, safer, and more affordable.” Balancing speed
and safety is not always easy. Many drugs are both life-saving, motivating
timely approval and release to the marketplace, and life-threatening, requir-
ing careful monitoring of safety and rapid action to address safety risks as
appropriate. The challenge in regulating prescription drugs is to weigh the
available evidence of efficacy and safety in the context of the prevalence and
severity of specific disorders, and the availability, safety and efficacy of other
approved therapies. Although FDA and the industry share an interest in
the discovery and development of beneficial products that improve health,
the decisions of regulators may affect the regulated industry’s success in the
marketplace (House of Commons Health Committee, 2005a,b).
Two dimensions of the external environment deserve more detailed dis-
cussion in the context of this report. These include the relationship between
FDA and the industry, which has been complicated by PDUFA, and FDA’s
relationships to Congress and to the White House.
The FDA–Industry Interface
It has become increasingly clear that the credibility of FDA is intertwined

with that of the industry it regulates. If FDA is viewed as less trustworthy to
make decisions that serve the public good, that may diminish the value and
meaning of FDA approval, casting a shadow of doubt on FDA-approved
products’ reliability, quality, and most importantly, their safety and effec-
tiveness. The concerns over drug safety described above have affected not
only FDA’s image, but that of the industry. In fact, the industry’s integrity
and its commitment to finding effective therapies for patients in need has
been questioned (PricewaterhouseCoopers, 2005). Industry’s credibility has
been considerably affected by judicial action in response to non-compliance
and by lawsuits related to how companies handled information about their
products and in particular, whether they were adequately forthcoming about
what they knew and when (Hensley et al., 2005; Kaiser Family Foundation,
2005; Wall Street Journal and Harris Interactive, 2005).
The user-fee funding mechanism established in 1992 to supplement
congressional appropriations helped to expand and strengthen preapproval
functions and the capabilities of the responsible CDER offices. PDUFA was
renewed and revised in 1997 and 2002 and will be considered for reau-
thorization in 2007. The user-fee program has increased considerably the
resources available for drug review (see Chapter 7) and made the review
process more predictable and expeditious (see Box 3-2 and Appendix C).
The Critical Path initiative is an example of FDA’s interest in supporting innovation in drug
discovery; it maps the way forward for applying cutting-edge science to drug discovery.

However, it has had some drawbacks, including increasing the agency’s de-
pendence on industry funding for its drug review activities, severely skewing
CDER’s focus to facilitating review and approval perhaps at the expense of
other center activities, and creating an environment of intense pressure on
its reviewers (Zelenay, 2005). A Department of Health and Human Services
(DHHS) Office of the Inspector General (OIG) survey of CDER staff found
that 40 percent of “respondents who had been at FDA at least 5 years in-
dicated that the review process had worsened during their tenure in terms
of allowing for in-depth, science-based reviews. Respondents cited lack of
time as the main reason” (DHHS and OIG, 2003).
In discussions with FDA staff, the committee learned that the emphasis
on timely review that is at the core of PDUFA and is linked with specific
performance goals has added to reviewer workloads despite the increase
in review staff. FDA must report to Congress annually about its success in
reaching the performance goals. Some observers have charged that increased
speed of review has led to decreased safety, in part because the time de-
mands of PDUFA limit the ability of reviewers to examine safety signals as
thoroughly as they might like (Sasich, 2000; Wolfe SM, 2006). Performance
goals with reporting requirements for actions relating to review speed, but
not for other actions, such as postmarketing safety monitoring and risk
communication, may lead to the assigning of higher priority to those actions
that have associated performance goals.
There has been some debate about PDUFA’s effect on drug safety as
demonstrated by drug withdrawals. Abraham and Davis (2005) found that
in the period before enactment of PDUFA the United States had 50 percent
fewer drug withdrawals than the United Kingdom largely because of the
longer periods that the FDA took to review drug applications. They sug-
gested that US efforts to speed approval may be compromising drug safety
in the PDUFA era. However, drug withdrawals are very rare occurrences
in general, and the total number of withdrawals in the last two decades of
the 20th century represents a modest figure that may not be useful for gen-
eralization. For example, in reviewing 20 drug withdrawals in 1980–2004
(nearly half of which occurred before PDUFA was enacted), the Tufts
Center for the Study of Drug Development found that “no trend emerges
between speed of approval and withdrawal” (Tufts Center for the Study
of Drug Development, 2005). Drug withdrawals are just one indicator of
drug safety; the timeliness of a withdrawal may be more important than the
fact of the withdrawal. Furthermore, drug withdrawals say nothing about
the safety of drugs that remain on the market and continue to affect public
health. Olson (2002) makes the point that drug withdrawal data are of
limited value in drawing inferences about drug safety more generally and
instead focuses on adverse drug reactions among all new chemical entities
approved between 1990 and 1995. The Government Accountability Of-

BOX 3-2
A Short History of the Prescription Drug User Fee Act (PDUFA)
1992
Use revenues from user fees to achieve certain “performance goals”
• Primary focus: decrease review times
PDUFA I Commitments:
• Complete review of priority original new drug and biologic applications
and efficacy supplements (90% in 6 months)
• Complete review of standard original new drug and biologic applica-
tions and efficacy supplements (90% in 12 months)
• Complete review of priority supplements (90% in 6 months)
• Complete review of standard supplements (90% in 12 months)
• Complete review of supplements that do not require review of clinical
data (manufacturing supplements) (90% in 6 months)
• Complete review of resubmitted new drug and biologic applications
(90% in 6 months)
1997
PDUFA II was reauthorized for 5 years (FY 1998–2002) as part of Title I of
the Food and Drug Administration Modernization Act
• Primary focus: decrease review times and shorten development
times
New PDUFA II commitments:
• Complete review of resubmitted efficacy supplements (90% in 6
months)
• Respond to industry requests for meetings (90% within 14 days)
• Meet with industry within set times (90% within 30, 60, or 75 days
depending on type of meeting)
• Provide industry with meeting minutes (90% within 30 days)
• Communicate results of review of complete industry responses to FDA
clinical holds (90% within 30 days)
• Resolve major disputes appealed by industry (90% within 30 days)
• Complete review of special protocols (90% within 45 days)
fice (GAO) analysis looked at withdrawals over 4-year intervals between

1985 and 2000, and found that the rate of withdrawals fluctuated from
4.39 percent in 1985–1988, to 1.96 percent in 1989–1992, to 1.56 percent
in 1993–1996, to 5.34 percent in 1997–2000 (GAO, 2002). There were
15 drug withdrawals between 1985 and 2000, and in its response to GAO,
FDA asserted that the variation in the withdrawal rate was probably related
to the small number of withdrawals in any given year (GAO, 2002). The
Berndt et al. (2005) analysis found that the proportion of approvals ulti-

• Electronic application receipt and review (in place by the end of FY

2002)
Changes in commitments
• Complete review of standard original new drug and biologic appli-
cations and efficacy supplements (90% in 10 months instead of 12
months)
• Complete review of manufacturing supplements that do not require
review of clinical data (90% in 4 months instead of 6 months if prior
approval is needed, otherwise 6 months)
• Complete review of resubmitted new drug and biologic applications
(90% of class 1 in 2 months, and 90% of class 2 in 6 months instead
of all in 6 months)
2002
PDUFA III was reauthorized for 5 years (FY 2003–2007) as part of Public
Health Security and Bioterrorism Preparedness and Response Act
• Focus: expand interaction and communication in IND phase and during
first cycle review
• Includes some funding for postmarket safety for 2–3 years after drug
approval for drugs approved after 2002
New PDUFA III commitments:
• Discipline review letters for presubmitted “reviewable units” of new
drug and biologic applications (90% in 6 months)
• Report of substantive deficiencies (or lack thereof) (90% within 15
days of filling date)
Changes to commitments:
• Complete review of resubmitted efficacy supplements (90% of class
1 in 2 months and 90% of class 2 in 6 months instead of all in 6
months)
• Electronic application receipt and review (enhanced by end of FY
2007)
SOURCES: FDA (1995, 2002, 2005e, 2006a).
mately leading to safety withdrawals prior to PDUFA and during PDUFA I

and II were not statistically significantly different.
The user-fee system has exacerbated concerns about the relationship
between FDA and the regulated industry by creating the appearance of con-
flict of interest in the regulators—critics assert that PDUFA gives sponsors
inappropriate leverage or influence over regulation because FDA is obliged
to please sponsors, now its “clients,” in return for fees for service (Grassley
et al., 2004; Harris, 2004; Wolfe S, 2006). Regulatory capture is a term used

by regulatory scholars (such as Stigler, 1971) to describe successful industry

pressure on regulators, and some observers actually believe that PDUFA has
facilitated the capture of FDA. The core problem in the relationship between
industry and FDA (leading FDA to consider industry a client) may lie in
the power of the industry to shape the scope and nature of PDUFA goals
(Olson, 2002; Carpenter et al., 2003; DHHS and FDA, 2005; Okie, 2005).
In the negotiations between FDA and the industry, Congress has given the
industry a considerable role in influencing what activities the user fees will
fund, thus limiting regulatory discretion and independence. In particular, fee
revenues only could be used to support activities designed to increase the
speed and efficiency of the initial review process. Fee revenues could not be
used to support postmarketing safety surveillance from 1992 to 2002. In
the 2002 PDUFA reauthorization, a small amount of fee revenues (about 5
percent) was permitted to be used for postmarketing drug safety activities;
however, restrictions on when these funds could be spent (only for drugs
approved after 2002, and for up to 2 years after approval, or up to 3 years
for “potentially serious drugs”) limited their effectiveness (Zelenay, 2005).
In Chapter 7, the committee discusses this troubling feature of PDUFA and
suggests an alternative.
Concerns about inappropriate influence on regulatory decision making
are not new, although it can be argued that PDUFA has made the connec-
tion between CDER performance and industry expectations much more
explicit. In 1977, a government panel examined whether there was pressure
on reviewers of new drugs to make regulatory recommendations favorable
to the industry (DHEW Review Panel on New Drug Regulation, 1977;
DHEW, 1977). The panel concluded that the problem was largely linked to
poor management rather than verifiable industry influence.
The second basic issue explored by the Panel was whether industry exerts undue
influence on FDA decisions. Many current and former FDA employees and
consultants had testified to Congressional committees that industry pressure
caused FDA officials to approve drugs that did not meet agency safety and effec-
tiveness standards and that those who attempted to oppose industry demands
were harshly and improperly treated by senior FDA officials. From detailed
investigations of these allegations by its staff, the Panel concluded that there
was no widespread use of improper influence by industry representatives. It did
identify several instances in which FDA supervisors unfairly disciplined dissent-
ing employees, but these lapses were found to result from poor management
rather than improper efforts of industry to control agency decision-making
[Dorsen and Miller, 1979:910].
Department of Health, Education, and Welfare, predecessor of the DHHS.

The concerns raised or exacerbated by PDUFA have an additional di-

mension. The interests of industry and the public are sometimes at odds,
and some critics fear that PDUFA may have increased FDA’s responsiveness
to one set of interests at the expense of the other set of interests, in some
circumstances. It is important to note that FDA’s various constituencies
have mixed expectations. The public, as reflected in the goals of multiple
consumer and patient advocacy groups, has a simultaneous desire for speed
and safety. Although the public wants to preserve the consumer protections
afforded by drug regulation in America, it also may demand earlier patient
access to potentially life-saving therapies, as was so effectively exemplified
in the successes of the AIDS treatment advocacy movement. The industry,
while developing a product that serves the public good by providing reliable
and effective therapies, has a superseding fiduciary duty to its sharehold-
ers—a duty that requires that it be profit-seeking and asset-conserving—so
its expectations are for smooth review and approval processes and the
fewest regulatory impediments. FDA itself is accountable to Congress,
whose members represent the American people. The committee believes
that FDA’s most important constituency is the public and that commitment
to the public good will ideally influence and check FDA’s interactions with
the industry.
Structural Factors, Policies, and Procedures

Structural Factors
External observers, from scientists to legislators, have noted that a

key organizational challenge for CDER is the striking disparities between
divisions responsible for premarket and postmarketing activities. There are
disparities in the formal role, authority, resources, and relative institutional
value conferred on the two groups of staff. Many of those issues have been
confirmed by the 2006 GAO report on FDA’s postmarket decision-making
and oversight process. The committee is not arguing that the responsibilities,
resources, and other features of OND and ODS/OSE must necessarily be
equal in every respect. The committee did not attempt to undertake a point-
by-point comparison of OND and ODS/OSE (roles, capabilities, resources
currently and in a perfect world), but it does assert that the formal function
and resources of ODS/OSE have not been commensurate with the impor-
tance of safety or with the tasks of monitoring postmarketing drug safety.
Inadequate management, discussed later in this chapter, also may contrib-
ute to the gap between ODS/OSE and OND and to the sense of interoffice
tension or, at best, disharmony between the two offices. To some critics,
the most concerning outcomes of the disparities between the premarketing

and postmarketing activities are that authority over postmarketing safety is

solely in the hands of people who did the work of reviewing and approving
a drug and that postmarketing safety activities appear to be secondary or
subservient to the premarket processes and the task of approving drugs for
marketing (Wolfe SM, 2006).
CDER’s culture seems to have been influenced by how premarket and
postmarketing functions have been divided historically. Randomized con-
trolled trials are the gold standard for studies leading to drug approval.
Epidemiologic, population-based studies are used after approval, when a
drug is on the market and being used in real-life circumstances. Medical
knowledge derives from both randomized clinical trials and epidemiologic
studies (including observational studies that use automated health care
databases), but the methods of the two approaches differ, as does the de-
gree of confidence that can be accorded analytic results. Although the two
approaches are complementary and can both be valuable depending on the
nature of the medical problem addressed—for example, population-based
studies provide different kinds of information that randomized controlled
studies do not deliver before approval—recent depictions of the workings
of CDER suggest that the disparate respect afforded to results of the differ-
ent approaches adversely affects interactions when uncertainties about the
data abound and the “call” regarding regulatory action is close. Most OND
reviewers are physicians who are trained to analyze prospective, random-
ized controlled clinical trial data, whereas the ODS/OSE staff, including the
safety evaluators and the epidemiologists, must typically work with uncon-
trolled or observational data. Most data bearing on safety issues generated
and reviewed in the postmarketing period are from case reports and from
epidemiologic studies. Recent controversies show that there is sometimes
a marked difference of opinion between OND and ODS/OSE about the
interpretation of such data. OND staff often view observational data as
“soft” and unconvincing, whereas ODS/OSE staff see them as informative
and carrying great weight in evaluating postmarketing safety questions.
The interdisciplinary tension is also an obstacle to full implementation
of a lifecycle approach to drug regulation, in which the preapproval process
actively and creatively involves anticipation of postapproval uncertainties
and a plan for addressing them. That is a clear example of how structure and
culture can connect. A structure that provides opportunities for crosscutting
discussion and methods—an interdisciplinary “team approach”—would
go a long way to encouraging a collaborative culture, in which differing
viewpoints and types of expertise can make a contribution.
In the last decade, there have been four major restructuring efforts in the
variously named office responsible for postmarketing safety and in CDER;
most recently, steps have been taken to clarify and elevate the previously
ad hoc role of ODS/OSE as part of a broader effort to “sustain a multi-

disciplinary, cross-center approach to drug safety” (Galson email to staff,

May 15, 2006; see also Appendix A). Although those efforts may reflect
CDER’s desire to improve the effectiveness of its safety surveillance pro-
grams, the frequency of repositioning organizational “boxes” and chang-
ing unit names raises concern that such changes are more cosmetic than
functionally effective responses to public dissatisfaction with the CDER’s
performance. Committee discussions with CDER staff and the history of
reports documenting problems in CDER suggest that previous efforts at
restructuring did not fundamentally alter the characteristics of or the rela-
tionship between OND and ODS/OSE or the morale and functioning of the
center. Thus, the committee is not convinced that the recent changes will
succeed without additional specific actions.
Policies and Procedures
The committee has reviewed the relevant CDER guidance documents

and the numbered documents in the Manual of Administrative Policies and
Procedures (individual documents are known as MAPPs) to understand the
current structure defining the roles of OND and ODS/ODE, and it reviewed
various congressional and public proposals for restructuring (CDER et al.,
2005; FDA, 2005d; Grassley, 2005; Johnson and US PIRG, 2005). The
committee has also discussed the technical or administrative details with the
appropriate FDA staff and managers, and reviewed reports describing the
many dimensions of drug regulation and its challenges (GAO, 2002, 2006;
DHHS and OIG, 2003; Thaul, 2005).
CDER constitutes teams for New Drug Application (NDA) reviews (see
Box 3-3). OND plays a formal lead role in most regulatory actions, and
OND reviewers sign components of the approval package; OND managers
(division directors, office directors, and the OND director) act in a final
A description of MAPPs is available at http://www.fda.gov/cder/mapp.htm.

CDER has issued several guidances and MAPPs related to the preparation of the review
package; several of these are mandated by the PDUFA. FDA’s guidance documents include the
following disclaimer: “This guidance represents the Food and Drug Administration’s (FDA’s)
current thinking on this topic. It does not create or confer any rights for or on any person
and does not operate to bind FDA or the public. You can use an alternative approach if the
approach satisfies the requirements of the applicable statutes and regulations. If you want to
discuss an alternative approach, contact the FDA staff responsible for implementing this guid-
ance. If you cannot identify the appropriate FDA staff, call the appropriate number listed on
the title page of this guidance . . . FDA’s guidance documents, including this guidance, do not
establish legally enforceable responsibilities. Instead, Guidances describe the Agency’s current
thinking on a topic and should be viewed only as recommendations, unless specific regulatory
or statutory requirements are cited. The use of the word ‘should’ in Agency guidances means
that something is suggested or recommended, but not required.” MAPPs, however, establish
procedures to be used (with variations, as appropriate) by CDER staff.

BOX 3-3
Composition of the NDA Review Team
Review teams include a review project manager (RPM) and primary
reviewers, who complete the discipline reviews, as needed, in the follow-
ing disciplines:
• Medical/clinical*
• Pharmacology/toxicology
• Chemistry manufacturing, and controls
• Biometrics/statistical
• Clinical pharmacology and biopharmaceutics
• Clinical microbiology
• Bioresearch monitoring.
*CDER documents appear to use the terms “medical review” and “clinical review”
interchangeably. It has been suggested that use of the phrase “clinical review”
indicates that a primary reviewer need not necessarily be a physician, although
most of them are. In this report we will use the more inclusive term “clinical review”
or “clinical reviewer.”
SOURCE: FDA (2005d).
decision-making capacity in most cases. Some members of the review team,

such as statisticians, work in offices other than OND. The committee has
learned that there is little integration of and a limited role for ODS/OSE staff
in the premarket review process; they work in a consultative and supportive
capacity and, with one exception, have no regulatory authority (CDER,
2005; GAO, 2006). Although postapproval responsibilities for ODS/OSE
have been growing, resources have improved only modestly (since 2004, a
growth from 94 to 132 full time equivalents dedicated to postmarketing
safety), and its formal role has not expanded.
FDA’s Guidance for Review Staff and Industry: Good Review Manage-
ment Principles and Practices for PDUFA Products (GRMP) outlines in
great detail the roles and responsibilities of the team leaders and reviewers
drawn from other disciplines in CDER. It also addresses so-called consults
from non-team members, such as staff from ODS/OSE, the Office of New
Drug Chemistry, and the Division of Drug Marketing and Communication.
The guidance document describes ODS/OSE staff as consultants, not as
members of the review team, and their formal responsibilities, other than

participating in consults, include participation in the preapproval safety

conference and review of product labeling. The only formal authority given
to ODS/OSE is to grant waivers to the industry sponsors of the postmarket-
ing reporting requirements in 21 CFR 314.80.
The PDUFA deadlines, which affect mostly OND staff, may play a role
in contributing to an organizational structure that limits ODS/OSE involve-
ment. Review packages accompanying an NDA approval letter include
what are called discipline reviews, often long documents written by CDER
scientists reviewing material in a specific scientific discipline submitted by an
applicant in support of the NDA. Discipline reviews and other documents
related to the review of a drug, such as the approval letter, are made public
on FDA’s Web site only if an application is approved for marketing (see
Chapter 4 for additional discussion). Review packages for products that are
not approved are not made public. The clinical review is usually written by
one OND staff person and includes summaries by the clinical reviewer of
other discipline reviews.
A policy and procedure (MAPP 6010.3, see Box 3-4) (CDER, 2004a),
the Clinical Review Template introduced in 2004, provides an opportunity
for formal involvement of ODS/OSE medical officers in the review process.
The purpose of the MAPP was to standardize the safety review components
of an NDA and in particular the approach to postmarketing safety of the
product (Racoosin, 2006). The MAPP suggests options for involvement
of more than one OND clinical reviewer. If there is more than one, a lead
reviewer is identified and has the responsibility for writing the overview and
section 4.3, which describes how the review was prepared. Two options ex-
ist for the final review; one allows for multiple reviews by multiple authors
incorporated into a single overview, and the other limits the review package
to one final clinical review with sections prepared by multiple reviewers.
Although there is no formal public documentation of changes instituted
by the MAPP, the committee’s informal review of NDA packages approved
before July 2004 suggests that the “Recommendation on Postmarketing
Actions” introduced a substantial change in the clinical review template by
creating a location in the review package for a review and recommendations
on postmarketing actions pertaining to the drug to be approved. Based on
a review of more recent NDA packages, it appears that the new template is
being used by reviewers of new drugs, but the committee believes that that
responsibility would be a reasonable and appropriate function for ODS/OSE
medical officers.
Management
There have been many opportunities for CDER and FDA leadership to
acknowledge to the committee and to others that there is a culture problem

BOX 3-4
Clinical Review Template—Postmarketing Actions
In July 2004 CDER issued MAPP 6010.3, the Clinical Review
emplate (CDER, 2004a), which established procedures for document-
T
ing the primary clinical review of NDAs. The clinical review is one of the
discipline reviews prepared in response to an original or supplemental
NDA (or Biologic License Application reviewed by CDER), amendments
in response to action letters, and efficacy supplements. The MAPP
describes the format of the discipline review and the responsibilities of
the reviewers, other team members, and those in the supervisory chain.
The review template includes 11 sections:
1. Executive Summary
2. Introduction and Background
3. Significant Findings from Other Review Disciplines
4. Data Sources, Review Strategy, and Data Integrity
5. Clinical Pharmacology
6. Integrated Review of Efficacy
7. Integrated Review of Safety
8. Additional Clinical Issues
9. Overall Assessment
10. Appendices
11. References
Section 9.3 of the template (part of Overall Assessment) is entitled

“Recommendation on Postmarketing Actions” and includes subsections
on “Risk Management Activity,” “Required Phase 4 Commitments,” and
“Other Phase 4 Requests,” and a review of and recommendations for the
applicant’s postmarketing risk management plan.
in CDER. However, although agency and center leaders generally mentioned

the flurry of drug safety activities being undertaken, they did not seem to
recognize the tensions and other strains within the center as anything more
than a minor distraction. On the basis of its discussions with current and
past FDA employees (both staff and management), and its review of several
government reports and other relevant literature, the committee believes
that CDER’s organizational culture is characterized by problems in several
important areas: a suboptimal work environment, a polarization between

two major functions, an underestimation and poor handling of scientific dis-

agreement and differences of opinion, a lack of consistency across divisions,
and instability and politicization at the top (in the Office of the Commis-
sioner). The committee believes that these issues may directly or indirectly
affect CDER’s handling of drug safety concerns.
A Suboptimal Work Environment
There is evidence of a persisting problem with retention, turnover, and

morale in CDER. CDER’s organizational culture does not seem to read-
ily embrace the values of staff participation, inclusion, and empowerment
that are generally thought to be essential to a healthy organization (Coffee,
1993). Relevant staff members are sometimes excluded from planning of
administrative and program improvements and their initiative in proposing
improvements is not well received (or “received” at all). Staff members are
sometimes left out of discussion and decision making about the future of
the center, new initiatives, etc.
Two government reports provide some information suggestive of po-
tential difficulties in the CDER work environment. A GAO report (GAO,
2002) on the rate of safety withdrawals after enactment of PDUFA found
that attrition among medical officers and other relevant FDA staff from
1998 to 2000 was noticeably greater than attrition in similar disciplines at
the National Institutes of Health and the Centers for Disease Control and
Prevention (10.5 percent vs. 5.5 and 4.7, respectively). Although one expla-
nation for the turnover is that FDA staff leave for promising opportunities
in industry (that arguably leads to a propagation of competent individuals
with regulatory agency experience throughout industry), it is possible that
turnover is indicative of a less-than-ideal organizational culture that requires
attention. The GAO report attributed the turnover to reasons that included
workload and decreased training opportunities. FDA data in a 2003 report
on the drug review process showed that medical officers and pharmacolo-
gists had the highest attrition rates in CDER (DHHS and OIG, 2003).
The committee learned from its conversations with OND staff that their
considerable workloads and time pressures exacerbated by PDUFA make it
difficult for them to be as thorough as they would like in their assessments
of safety after marketing. The committee’s discussions with CDER staff
resonated with the findings of previous assessments—reviewers of new drugs
are often overwhelmed merely keeping up with the routine aspects of review,
which leave little time to consider postmarketing safety plans thought-
fully, or to investigate (for example, with colleagues in other disciplines)
safety signals that arise after approval (IOM Staff Notes, 2005–2006). In
such circumstances, it is little wonder that professional development and

internal interaction to facilitate communication and understanding among

divisions and offices become luxuries. In 2005, a group of OND medical
officers organized itself to identify possible causes of attrition and to make
recommendations to CDER management about ways to improve retention
(Medical Officer Retention Subcommittee, 2006). The group’s recommenda-
tions included addressing OND reviewer workloads by hiring more staff,
increasing division and office director awareness of reviewer needs, rede-
fining the CDER vision, and in general transforming the CDER leadership
philosophy. Members of that staff subcommittee expressed concern that the
leadership philosophy in CDER did not encourage staff participation and
input at all levels (Medical Officer Retention Subcommittee, 2006).
The failure of management to implement effective changes to address
those important issues indicates that there is a problem. ODS/OSE and
OND staff have reported being left out of regulatory meetings directly
related to their work, and ODS/OSE staff have frequently been left out of
relevant advisory committee meetings (GAO, 2006). There is evidence of a
lack of consistent processes to facilitate and resolve safety issues identified
by ODS/OSE and passed on to OND. The 2006 GAO report’s finding that
ODS/OSE consults and questions often went into a “black hole” and that
initiating staff never received feedback is consistent with what this commit-
tee learned.
Some staff-generated ideas for process or culture improvements ap-
peared to receive little or no attention from management. In its 2006 re-
port, GAO noted that in December 2004, ODS epidemiologists requested
a broadening of their role to include “presenting all relevant ODS data at
advisory committee meetings” but management did not respond (GAO,
2006:22). To the best of the present committee’s knowledge, CDER man-
agement also did not respond to the OND Medical Officer Retention
Subcommittee’s May 2005 proposal until June 2006. The committee was
surprised to find out that although the Drug Safety Oversight Board (DSB)
had been introduced to a variety of audiences (Congress, the public, etc.),
some CDER staff seemed uninformed about what the board was expected
to accomplish and how it could affect their work.
Management scholars have identified a strong attachment to the status
quo in many organizations and a tendency to commit “sunk cost” errors by
pursuing a course of action because so much has already been invested in
it (Edmonson et al., 2005). A panel convened by the National Aeronautics
and Space Administration after the Columbia disaster identified similar
organizational tendencies, noting, for example, that “once the Agency is
on record as committed to a specific achievement, it becomes unpalatable
to back off of that target for fear of appearing to fail” and that there was
an attitude of “comfort with existing beliefs” that justified a resistance to

internal or external criticism and a stifling of dissenting views (Return to

Flight Task Group, 2005; O’Leary, 2006). The perception that there are
somewhat similar cultural attitudes in CDER is evident in the concerns of
consumer advocates and academics and confirmed by the DHHS OIG and
GAO reports that new drug reviewers feel pressured by the unstated expec-
tations of the agency leadership (due to PDUFA goals and other reasons)
to approve drugs and are unable to revise the regulatory approach to an
already-approved drug.
Interoffice Polarization
The committee has seen evidence of a divide between the premarketing

and postmarketing staff in CDER (generally represented by staff in OND
and staff in ODS/OSE, respectively). ODS/OSE staff has been left out of
regulatory discussions and advisory committee meetings (GAO, 2006;
IOM Staff Notes, 2005–2006). The user-fee funding system may have also
allowed (or at least exacerbated) the emergence of a major resource gap
between OND and ODS/OSE (IOM, 2005; IOM Staff Notes, 2005–2006;
Zelenay, 2005; GAO, 2006) (also see Chapter 7 for a more detailed dis-
cussion of the funding and staff imbalance). Although the committee did
not explore the history of this divide, conversations with CDER leadership
revealed disparities in how the two offices and their contributions to the
agency’s work are regarded. The 2006 GAO report has also confirmed the
difference in status between the two offices. Given the high-profile concerns
about drug safety, the fact that an office bearing the title of “Drug Safety”
had a lower status than an office of “New Drugs,” and agency spokesper-
sons appeared dismissive of the work of staff in that office may have also
exacerbated the perception of tension (Harris, 2006b). The committee is
aware that there have been repeated attempts to reorganize or restructure
CDER, both by moving boxes around a chart and by developing internal
policies, procedures, and guidance documents (as described above), but
culture problems have persisted.
The committee has seen little historical evidence of successful initia-
tives to strengthen ODS/OSE capabilities or to stabilize the office, which
has experienced eight changes in leadership and four reorganizations in the
past 10 years (GAO, 2006). Although the committee was encouraged by the
appointment of a new permanent ODS/OSE director (after much turnover
in that position [GAO, 2006]) and by evidence of planning to improve
communication and collaboration between OND and ODS/OSE, it remains
concerned that these attempts are “too little, too late.”
The committee believes that management in CDER has not done enough
to cultivate an atmosphere of mutual respect and appreciation across some

of the disciplines. In interactions with CDER leadership, the committee

formed the impression that ODS/OSE staff have been considered marginal
players, compared with OND staff, in contributing to the work of ensur-
ing drug safety. When the committee inquired about the apparent cultural
divide in discussions with CDER leadership, it heard that ODS/OSE was not
capable of a greater function in postmarketing safety because of a lack of
qualified and trained staff, a lack of analytic sophistication, and inadequate
understanding of the data and their weighing in the approval process. The
committee also heard that problems between ODS/OSE and OND are simply
a squabble, not warranting management attention. The GAO report (2006)
appeared to touch a nerve when it interpreted ODS/OSE’s role of consultant
to OND as secondary, not well defined, and lacking clear responsibilities.
In its response to GAO, FDA argued that the consultative role is important
and that the GAO report did not recognize that; but the agency did little
to explain specific steps it would take to clarify the role of ODS/OSE and
to pay more than lip service to its contributions. The committee acknowl-
edges that some recent changes have occurred in CDER. Some have been
on ODS/OSE’s own initiative—as the GAO report has acknowledged, the
level of expertise and sophistication of analyses conducted by the office have
evolved, and a promising new leader has been appointed to head the office
(FDA News, 2005; GAO, 2006). As noted in Chapter 1 and in Appendix
A, in the wake of highly publicized concern about the safety of some drugs
approved by FDA, the agency and CDER announced the implementation
of several strategies to improve attention to postmarketing safety and to
strengthen the administrative processes that underlie drug safety work in
FDA. Those strategies included two processes for dispute resolution at the
staff level, and the establishment of the DSB for interdivisional difficulties
(discussed below) (CDER, 2004b; CDER and FDA, 2005).
It does not appear that the various efforts to restructure CDER have
improved interactions between review and postmarketing staff. The dispute
resolution mechanism has yet to be used, and mass media reports about
emerging drug safety concerns continue to give the appearance that the
center is not managing those concerns adequately. On several occasions
when the findings of safety staff have been cited in the mass media, agency
spokespersons have downplayed or disparaged the information’s quality
or completeness, instead of assuring the public that the agency takes the
concerns of its staff seriously and that staff collaborate to bring such im-
portant questions to resolution. New documents to guide CDER staff have
not necessarily translated into greater clarity and effectiveness at the level
of interoffice relationships and procedures; in fact, there is a continuing lack
of established mechanisms for communicating about and following safety
signals between offices. That attitude was apparent on numerous occasions
when members of this committee spoke with FDA and CDER management

who described ODS/OSE as lacking in needed expertise, sophistication,

and depth of experience (IOM Staff Notes, 2005–2006). That disparity
in management attitudes toward OND and ODS/OSE is also suggested by
information provided in the 2006 GAO report, in the comments of FDA
officials to the press, and in a recent response from the CDER director to
an internal group’s proposal to address medical officer attrition. May and
June 2006 newspaper articles about the agency’s handling of drug safety
concerns about an antibiotic indicated that some postmarketing safety staff
expressed concerns that were not addressed in a timely manner by CDER
management. An FDA spokesperson described a safety reviewer’s report
of her concerns “a preliminary, raw assessment” and stated that “the final
decision will be made by experts who have the full benefit of a large section
of opinion and scientific fact” (Harris, 2006a).
Underestimation and Poor Handling of Scientific Disagreement and

Differences of Opinion
Management’s difficulties in addressing internal agency conflict and

scientific disagreement transparently and competently, in communicating
scientific uncertainty to diverse audiences effectively have played an impor-
tant role in damaging the credibility of CDER and the FDA. As discussed
in Chapter 4, the regulation of drugs rests on a foundation of incomplete
but growing knowledge, and the risk-benefit assessment for every drug
continues to evolve after approval, when use of the drug moves from the
carefully controlled confines of clinical trials to the largely uncontrolled and
much more complex circumstances of real-life prescribing and use. Legiti-
mate scientific disagreement may occur at various points in the lifecycle of
a drug. There may be disagreement about whether a reasonable threshold
of certainty has been reached to justify approval (the absence of standard
approaches to the risk-benefit assessment before approval is discussed in
greater detail in Chapter 4). After approval, there may be scientific disagree-
ment about the interpretation of adverse event signals (for example, there
is no clear guidance on when a noise becomes a signal) and about what
regulatory action is warranted.
The committee is concerned about information suggesting that scientific
disagreement in the center is sometimes handled in ways that may create
an inappropriate atmosphere of pressure or poor tolerance of disagreement.
The 2003 DHHS OIG report of survey findings on 401 CDER reviewers
(most in OND) stated that “18 percent of respondents indicated that they
have felt pressure to approve or recommend approval for a drug, despite
reservations about its safety, efficacy, or quality” (18 percent accounts for
about 72 of 401 respondents to the survey). Although scientific disagree-
ment is understandable and there are cases where a division or office director

disagrees with a reviewer’s recommendation on the basis of the science, hav-

ing even one or two staff members who report pressure to approve or recom-
mend approval is an entirely different and deeply troubling occurrence.
In its visit and later discussions with FDA staff, the committee learned
that differential valuation of disciplinary approaches affects the relationship
between OND and ODS/OSE and contributes to a perception in each office
that its counterpart does not have the full picture or does not give enough
consideration to colleagues’ different disciplinary perspectives. Although
OND staff includes physicians, some of whom have training in statistics or
epidemiology, their efforts are oriented substantially toward review of data
from randomized controlled trials, and their experience with and confidence
in epidemiologic studies may be slight. ODS/OSE staff, in contrast, have a
greater level of comfort with epidemiologic approaches but less familiar-
ity with randomized controlled trials and their analysis. But as mentioned
above, the imbalance in formal role and authority between the new drug
review staff and surveillance and epidemiology staff denotes subservience of
the safety function, and a management devaluation of the latter discipline
and approach.
The DSB, which consists of staff members of several CDER offices
and representatives of other FDA centers and other government agencies
is established to “improve public knowledge of emerging important drug
safety concerns; strengthen internal drug safety management; foster practi-
cal policy development to improve consistency and timely resolution of
important drug safety concerns; and provide a standing venue for resolution
of CDER organizational disputes” (Cummins, 2006). Including members
drawn from CDER offices not primarily responsible for any given product
or issue, and from other federal agencies, is intended to provide some inde-
pendent oversight regarding emerging issues while maintaining the ability to
convene quickly without conflict-of-interest considerations or concern about
the discussion of proprietary matters. Items for discussion can be brought
to the DSB by a CDER division or by OND or ODS/OSE leaders. It is not
In August 2006, the Union of Concerned Scientists (UCS) and Public Employees for Envi-
ronmental Responsibility released their survey of FDA, which included the survey instrument
used in the 2003 DHHS OIG survey. UCS findings echoed those reported by OIG in 2003,
including the response to “Have you ever been pressured to approve or recommend approval
for an NDA despite reservations about the safety, efficacy, or quality of the drug?” Of 217
CDER staff who responded to this question, nearly 19% (41) said “yes” (UCS, 2006a,b). Af-
ter the UCS release, FDA Acting Commissioner Andrew von Eschenbach met with UCS staff,
acknowledged his concern about the issues related to morale identified in the survey, and also
vowed to work to create “an environment where there is free, open and vigorous debate and
discussion” (UCS, 2006a,b). In the course of Senate committee questioning during the August
1, 2006, nomination hearing, Dr. von Eschenbach was asked about the UCS survey question
regarding “pressure to approve . . . despite reservations.” The acting commissioner stated that
“no one should ever alter the data or the scientific facts” (von Eschenbach, 2006).

clear whether DSB can on its own initiative address an issue of which it has
become aware if it is not formally referred to them. The DSB emerged as part
of the agency’s response to congressional and public concern over highly
publicized drug safety problems. Because many critics called for independent
external oversight of drug safety, the creation of the board was believed by
some to be a solution to address that particular concern (FDA, 2005c). The
composition of the board caused confusion and gave rise to criticism that
the board as constituted was not independent. That confusion was furthered
by FDA’s silence on the board’s actual (and potentially useful) function, and
the underlying public and legislative concern about independence was left
unaddressed. Because the DSB has been in operation for only a short time,
it is too early to judge its effectiveness, but some of its drug safety problem
resolution, management, and policy functions seem to constitute a sensible
approach. DSB is analogous to industry practices of bringing together lead-
ers of different groups in a company to consult with a group facing a difficult
problem. However, the committee believes that the external communication
function of the board seems to be a vastly different and equally important
set of concerns that should be handled by a different entity in CDER (see
Chapter 6). That would allow the DSB to focus its energies and resources
on addressing the internal management of drug safety issues.
There has been additional confusion about the apparent overlap between
the Drug Safety and Risk Management Advisory Committee (DSaRM) and
DSB. CDER management has described the latter as a “venue for resolv-
ing CDER organizational drug safety disputes” and “discussing [the] need
for AC [advisory committee] meetings about emerging safety information”
whereas DSaRM has been described as a way to obtain public input and fa-
cilitate discussion to inform CDER decision making. The committee believes
that DSaRM fulfills the function of the sought-after independent, external
safety advisory and review body, in contrast with DSB, which is intended to
bring serious and complex internal safety issues to resolution.
Inconsistency
Many interactions in CDER appear to be idiosyncratic and personality-

driven. The committee understands that there is great variation within and
among drug classes and from one product to another and that flexibility is
desired. However, there seem to be subjects on which consistency would be
beneficial, for example, methods of risk-benefit analysis, preapproval deci-
sions on postmarketing studies, handling of disagreements between offices,
ODS/OSE participation in the review process, monitoring of drug safety
signals after approval, responding to drug safety signals, communication of
important risks to the public, and followup of postmarketing study commit-
ments. Some best practices have not been disseminated throughout CDER.

For example, one division’s model for ensuring internal safety capacity by
establishing its own safety team of epidemiologists has attracted interest in
CDER and from drug safety advocates but has not yet been replicated in any
other division (the committee has heard that this model may be expanded
to other divisions).
Instability and Politicization at the Top
The absence of stable leadership at the commissioner level and lack of

consistent oversight of CDER by the commissioner may have contributed
to overarching management problems in CDER. Although the day-to-day
work of CDER is not immediately affected by what is happening in the com-
missioner’s office, the recurring absence of a confirmed commissioner has
implications for the agency. First, the absence of stable leadership has meant
much more than going without an agency figurehead. As discussed above,
the external environment places great pressure on FDA and its centers, and
the agency’s top leadership plays a crucial role in setting the course for the
agency and in mediating the effects of external pressures by representing
the agency in interactions with other government agencies, Congress, the
industry, and the public. An acting commissioner does not carry the same
weight symbolically, and lacks the authority to articulate agency positions.
PDUFA reauthorization talks in 2002 were reportedly slowed down by the
lack of a commissioner (Validation Times, 2002). An individual in an acting
capacity also may be unable to act decisively; such a person would likely
defer making any difficult decisions or setting a new course for the agency.
Furthermore, staff may be unlikely to take such a leader seriously because
an acting position is by its very definition temporary (Miller, 2006; Ross,
2006). In cases when an acting commissioner is also the president’s nominee
facing the prospect of challenging Senate hearings, making decisions on
high-profile issues could potentially complicate the road to confirmation.
As appointing and confirming a permanent commissioner is delayed, FDA
staff and the public may also conclude that their government does not con-
sider a commissioner’s position important, and that may have demoralizing
consequences on staff and affect the agency’s credibility (Kaufman, 2004b;
Alonso-Zaldivar, 2006).
Industry leaders have asserted that the lack of a leader leads to an
increase in agency caution and a decrease in predictability in the eyes of
companies and investors (Young, 2005). In 2002, the Biotechnology In-
dustry Organization (BIO) petitioned President George W. Bush to appoint
That is the Neuropyschiatry Drug Products Division was recently split into two, a Neurol-
ogy Products Division and a Psychiatry Products Division. The safety team currently resides
in the Division of Neurology Products but supports both divisions.

a commissioner, arguing that the industry and the nation needed “strong
leadership from an FDA commissioner with vision and experience in science,
medicine and administration” (BIO, 2002). In the same year, the PhRMA
president and CEO reported that the industry was challenged by the absence
of agency leadership and that PDUFA negotiations were slowed down by
the absence of a commissioner (National Journal’s Congress Daily, 2002;
Validation Times, 2002). Former commissioner Jane Henney stated that in
the absence of leadership, “industry loses because it needs predictable and
strong signals about the review process, the consumers need to make sure
somebody is in charge and the FDA staff needs somebody who can take the
heat if necessary” (Kaufman, 2004a). In 2002, FDA staff were questioned
in a congressional hearing without the support of a Senate-confirmed com-
missioner (Kaufman, 2004a). In the 2005 Senate committee session on the
nomination of the then Acting Commissioner, Senator Enzi cited a letter
from the Senate committee to the president urging the nomination of a
commissioner “to provide the agency with greater clarity and certainty in
its mission,” and stated that a “fully confirmed Commissioner is essential
to ensuring that these medical breakthroughs can be brought to the market
safely and effectively. Consumers deserve to have a fully functional FDA
that can oversee the industry with confidence and authority and harness the
technical achievements that can improve and save lives” (Senate Executive
Session, July 18, 2005).
Management literature has made it clear that organizations, including
government agencies, cannot function well without effective leadership to
set them and keep them on course to achieve their mission (GAO, 1996).
In the last 30 years, FDA has had eight commissioners and seven acting
commissioners (including the current acting commissioner) or, when the
post was vacant, an acting principal deputy commissioner. The eight com-
missioners have served an average of 2.5 years with a range of 2 months to
6.3 years (FDA, 2006b). That instability is thought to have contributed to
CDER’s problems. CDER is the largest center in the agency, the center direc-
tor reports to the commissioner, and the center’s decisions and their reper-
cussions are highly visible and sometimes controversial, as was the case with
the Plan B over-the-counter switch application (GAO, 2005). The committee
believes that turnover and instability in the commissioner’s office leave the
agency without effective leadership or the potential to emphasize safety as
having high priority in the work of the agency. Without stable leadership
strongly and visibly committed to drug safety, all other efforts to improve
the effectiveness of the agency or position it effectively for the future will be
seriously, if not fatally, compromised. A priority for the agency should be to
regain the trust of the public while positioning itself for the future.
The controversy over the emergency contraceptive Plan B has further
highlighted the power of the commissioner. In this area, the political environ-

ment interfaces with issues of leadership. Plan B, a prescription emergency

contraception drug, was approved in 1999. In 2002, FDA staff met twice
to discuss and prepare for the sponsor’s expected application for a switch of
Plan B from prescription to over-the-counter (OTC) status. In April 2003,
the sponsor submitted its supplemental NDA for the OTC switch, and
FDA set a PDUFA goal date of February 2004 (for a total of 10 months, a
typical timeline for a standard review) to reach a decision on the applica-
tion. A joint meeting of the two relevant advisory committees—those for
non-prescription drugs and for reproductive health drugs—concluded with
a vote that overwhelmingly favored an OTC switch (GAO, 2005). However,
the agency denied the application, raising questions about the basis for that
decision making. In the end, it became clear that the ultimate decision was
made in the Office of the Commissioner for reasons that were not clearly
linked with a scientific rationale. The perception of political considerations
overruling scientific judgment, even just in a single case, inevitably raises
concerns about the legitimacy of decision making in every case.
Proposed Solutions to CDER’s Organizational Dysfunction

Management
On the basis of its review of relevant government reports, conversations

with present and former FDA staff and managers, and its examination of
CDER guidance and policies and procedures documents, the committee
finds that CDER’s organizational culture is under great strain and that
change is needed to ensure that the center can fulfill its components of the
FDA mission. The last several years of newspaper articles about FDA and
CDER specifically and relevant public opinion polls have shown a decline in
FDA’s credibility with the public, some scientists and academics, and others.
Over the years, there have been multiple initiatives, taskforces, and panels
on CDER’s work and multiple government reports identifying problems and
recommending solutions. The fact that many substantial changes have not
been made may be a primary symptom of management failure, a lack of
leadership, and of a lack of appropriate oversight by Congress.
According to management research, organizational cultures that are
constructive or healthy are more effective in accomplishing their mis-
sion. But cultural change may take many years to implement and requires
sustained and comprehensive effort (GAO, 1996; Khademian, 2002). As-
sessments of federal agency management have found that when federal
executives reorganize agencies, organizational culture is rarely a focus of
attention—it is often an afterthought or considered a nicety irrelevant to
the complex and technically challenging work of many government agen-

cies (Khademian, 2002). In that regard, FDA is no different. The consistent

neglect of cultural problems in the organization betrays a lack of recognition
of the importance of healthy culture. Even if FDA and CDER leaders do
not see themselves as managers who stifle dissent or exclude participation
from staff, that perception clearly exists (affecting agency credibility), and
problems with retention and morale confirm it.
Agency Leadership
Healthy organizations require effective and stable leadership. The com-

mittee believes that there is an urgent need for a full-time, confirmed FDA
commissioner who will be visible and forceful in creating a culture of safety
by facilitating a systematic, science-based approach to continually assessing
and acting on risk-benefit during the lifecycle of every drug (pre- and post-
approval). The commissioner’s role is also to provide effective oversight
of CDER, particularly given the strong external pressures on the center’s
work. Many observers from industry and from the scientific community
have expressed concern in recent years that the commission position has
remained unfilled or filled by deputy commissioners functioning as acting
commissioner for long periods of time.
The committee recognizes that the daily work of FDA staff may not
be strongly affected by what happens in the office of the commissioner, but
there is fairly widespread agreement, described above, that the absence of
a commissioner has been a problem because without a legitimate, Senate-
confirmed leader, it is harder for the agency to define and achieve its strategic
vision.
The committee wishes to emphasize that in making the following rec-
ommendations, it does not imply that politics can or should be removed
from a top scientific position, such as the FDA commissioner. However,
it is important to the credibility of a science-based regulatory agency that
scientific evidence, not solely political considerations, prevail in cases
where high-profile regulatory decisions must be made. The Plan B decision
described above may have undermined the agency’s credibility, as evidence
In 1996, Congress asked GAO to determine whether performance problems at the Federal
Aviation Administration were related to its organizational culture. GAO found that the cul-
ture impeded the agency’s work. Characteristics highlighted included a system of bureaucratic
incentives that rewarded staff who preserved the status quo and punished those who identified
problems (GAO, 1996). Assessments of government agency performance and examples from
the management literature have shown repeatedly that organizational cultures that stifle dis-
sent, exclude staff from decisions about the organization’s vision, and allow cultural problems
to linger unaddressed are not healthy cultures, and those problems interfere with their ability
to achieve their goals (Weick and Sutcliffe, 2001; Heifetz and Laurie, 1998; Khademian, 2002;
Return to Flight Task Group, 2005; O’Leary R, 2006).

emerged that the basis for decision making was not scientific, but other
types of considerations (Bridges, 2006; Rockoff, 2006; Washington Drug
Letter, 2006).
Finally, the committee believes that a fixed-term appointment for the
FDA commissioner may help to lessen turnover. Reports from GAO and
from the National Academy of Sciences (NAS) have found that turnover in
government agency leadership is linked with a focus on short-term goals and
uncertain accountability and that fixed terms for presidential appointments
help to ensure stability and strengthen an agency’s leadership (GAO, 1996;
GAO, 2003). Currently, presidential appointment with Senate confirmation
positions for fixed terms include: surgeon general of the Public Health Ser-
vice, 4 years; director of the National Science Foundation (NSF), 6 years;
commissioner of the Bureau of Labor Statistics, 4 years; under secretary
for health in the Department of Veterans Affairs (also the Chief Executive
Officer of the Veterans Health Administration), 4 years; commissioner of
the Social Security Administration, 6 years; and commissioners of the Fed-
eral Communications Commission, 5 years. Another NAS committee that
recommended a 6-year term for the National Institutes of Health (NIH)
director concluded that the NSF director’s 6-year term “has been a good
model for creating a system of accountability and periodic review that has
the possibility of transcending changes in administration” (NRC, 2003).
Fixed terms can vary in length, be renewable or not, and have more or
less strict terms of removal, depending on the degree of insulation desired. In
all cases, to be constitutional, the president must retain the power of remov-
al—incumbents of term appointments should be accountable and subject to
removal by the president. On the one hand, establishing a term appointment
and specifying the reasons for which an appointee may be removed changes
the terms of removal to some extent. It creates a presumption that individu-
als in these positions should stay rather than be automatically removed with
every change in administration, and it requires an administration to give
good reasons for such a removal. On the other hand, the use of terms also
indicates that there should be periodic turnover—not for partisan reasons
but to ensure new blood and fresh ideas.
3.1: The committee recommends that the FD&C Act be amended

to require that the FDA Commissioner currently appointed by the
President with the advice and consent of the Senate also be ap-
pointed for a 6-year term of office. The Commissioner should be
an individual with appropriate expertise to head a science-based
agency, demonstrated capacity to lead and inspire, and a proven
commitment to public health, scientific integrity, transparency, and
communication. The President may remove the Commissioner from

office only for reasons of inefficiency, neglect of duty, or malfea-

sance in office.
Given the influence of the social, policy, and economic environment

on CDER’s work and its major structural and management challenges, the
committee believes that a confirmed commissioner will need support to
effect organizational change, particularly with respect to CDER. The com-
mittee believes that a mechanism to support the commissioner is necessary
because transforming an organization’s culture requires relevant leadership
and management expertise and sustained effort.
3.2: The committee recommends that an external Management

Advisory Board be appointed by the Secretary of HHS to advise
the FDA commissioner in shepherding CDER (and the agency as
a whole) to implement and sustain the changes necessary to trans-
form the center’s culture—by improving morale and retention of
professional staff, strengthening transparency, restoring credibility,
and creating a culture of safety based upon a lifecycle approach to
risk-benefit.
Although the committee is not aware of entities analogous to what it

is recommending, it is worth noting that NIH has an Advisory Committee
to the Director, which advises the agency head on major plans and policies,
including those related to resource allocation, program development, and
“administrative regulation and policy” (NIH, 2006). The external Manage-
ment Advisory Board to the FDA commissioner would operate under Feder-
al Advisory Committee Act rules. The secretary of HHS should consult with
an independent organization in identifying candidates to ensure that the
board’s composition is appropriate for the task, including familiarity with
the regulatory system for drug development and FDA’s role in it and proven
experience in successfully managing culture or organizational change.
(Ideally, conflict-of-interest concerns would be addressed by ensuring that
a majority of board membership should have no substantial personal finan-
cial interest in the pharmaceutical industry, and board members should not
be selected from current pharmaceutical industry representatives.) Board
Two examples of independent advice in identifying members of Federal Advisory Com-
mittees: DHHS consults with the NAS on the composition of the National Vaccine Advisory
Committee, and the Consumer Product Safety Commission appoints a Chronic Hazard Ad-
visory Panel of independent scientific experts from nominations submitted by the president
of the NAS.

members would serve staggered 3-year terms that may be renewed once.
The board would meet no less frequently than twice a year.
The Management Advisory Board would assist FDA and CDER in their
efforts to understand how organizational culture in the center is shaped by
the environment, by a legacy of structural imbalance, and by management
problems. The committee has learned that a variety of promising steps have
been taken to improve interactions among offices, evaluate and improve in-
ternal processes, and even familiarize disciplines with one another. However,
given CDER’s long history of reorganizations, external studies, and fitful
change initiatives, the committee is not optimistic that current efforts will
be sustained without the absolute commitment of managers and of center
and agency leaders to act on many different levels, with broad staff partici-
pation and input and in an atmosphere of openness, and to be “relentless”
in creating, seizing, and sustaining opportunities for change (Khademian,
2002:126). The committee believes that it is imperative that the director
of CDER, with support from the commissioner and the assistance of the
Management Advisory Board, take immediate steps to strengthen leader-
ship, organization, and function to create and visibly champion a culture
of drug safety in the center.
3.3: The committee recommends the Secretary of HHS direct the

FDA commissioner and Director of CDER, with the assistance of
the Management Advisory Board, to develop a comprehensive
strategy for sustained cultural change that positions the agency to
fulfill its mission, including protecting the health of the public.
As part of the strategy for cultural change, the director of CDER should
establish an effective organizational development capability in CDER by
forming a staff working group consisting of people who represent diverse
disciplines, roles, and viewpoints and including one or two staff members
with organizational development expertise. The group would work with
and support the center director in providing meaningful opportunities for
two-way communication with staff, identifying and addressing culture
problems, and nurturing a culture that values disagreement and thinking
outside the box.
Structural Factors
The imbalance in authority, formal role, and resources between OND

and ODS/OSE constitutes a major obstacle to a healthy organizational cul-
ture in CDER. On the basis of the rationale described above, the committee
sets forth its recommendation to address the cultural challenges exacerbated
by the existing structure.

The aforementioned development of MAPPs as the primary strategy

to manage how OND and ODS/OSE interact and to document differences
of professional opinion may indicate that using procedural modifications
to mollify critics is easier than engaging in the hard work of transforming
a culture to embrace scientific disagreement and dissent and handle them
in a constructive and transparent manner. Organizational literature shows
that the bureaucratic cultures of public organizations are frequently rigid,
authoritarian, and oriented toward obeying orders rather than toward in-
novation and independent thought (Kets de Vries and Miller, 1986; Claver
et al., 1999; Khademian, 2002; O’Leary, 2006). That could explain why
it is so easy to turn to policy and procedure development. However, it is
important to note that the inflexibility and conformity that characterizes
some government agencies are at least in part created by the requirements
of Congress and the Office of Management and Budget. As described above,
creating a healthy organizational culture in CDER depends on more than the
efforts of management and staff—the external environment, including the
top levels of the executive branch and relevant congressional committees.
The tension between the approaches of CDER professionals who focus
largely on the premarketing period of a drug’s lifecycle and those who deal
with the postmarketing period is not unusual (consider, for example, areas
of scholarship where the practitioners of quantitative and qualitative meth-
ods come in conflict). However, the friction has often been unconstructive,
particularly when the goal is to achieve close integration of the two ap-
proaches, and to facilitate an atmosphere of mutual respect and appreciation
between the two sets of disciplines involved. Facilitating such a shift, from
an uneasy relationship to a collaborative and constructive one, requires
skilled management and leadership.
The committee believes that a public health orientation and a lifecycle
approach to understanding and minimizing the risks posed by drugs is
best served by better and formal integration of the OND and ODS/OSE
perspectives. The committee understands that new drug review and ap-
proval are undertaken with a matrix team approach, however it notes with
concern the lack of formal participation of ODS/OSE in the review team.
That might reflect a sentiment in CDER that ODS/OSE has only incidental
contributions to make to the intellectual basis of new drug review and to
recommendations about postapproval regulatory actions. A strengthened
ODS/OSE would have much to contribute.
The committee believes that in keeping with the goal of an integrated
lifecycle approach to considering drug safety, mechanisms for anticipating
potential postmarketing safety issues at the time of approval can be formal-
ized and strengthened. Although OND retains authority over approval deci-
sions, the committee believes that ODS/OSE’s role in the approval process
needs to be formalized, specifically in the area of postmarketing safety.

3.4: The committee recommends that CDER appoint an OSE staff

member to each New Drug Application review team and assign
joint authority to OND and OSE for postapproval regulatory ac-
tions related to safety.
To formalize the changes recommended above, CDER’s GRMP should

be modified as appropriate. The ODS/OSE team member should be respon-
sible for formal review of and comments on the clinical reviewer’s “Inte-
grated Review of Safety” (Section 7 in the Clinical Review Template) and
for authoring the “Recommendation for Postmarketing Actions” (Section
9.3 in the Clinical Review Template).
Through their active and formal participation in the NDA review pro-
cess, ODS/OSE staff members would develop a fuller appreciation of the
risks as well as the benefits associated with a drug, which some have stated
they do not now have because of their exclusive focus on postmarketing
safety. That appreciation would strengthen their evaluation and advice on
postmarketing safety actions, which have been described as too risk-averse
and lacking in understanding of the efficacy data and clinical context, that
is, the benefits of the drug to individual patients. In addition, active par-
ticipation could lead to better communication and understanding between
the clinical reviewers and the epidemiologists, who have been described
as “speaking different languages.” The committee believes that following
this recommendation would help to break down cultural barriers between
OND and ODS/OSE as staff work together on integrated review teams with
the common goal of evaluating and ensuring drug safety and efficacy over
a product’s lifecycle. However, bringing the two types of staff together in
teams is not sufficient to facilitate mutual understanding and appreciation.
Additional efforts are needed to apply this ethos to all interactions between
pre- and postmarketing, and OND and ODS/OSE staff. The committee was
pleased to learn about plans in ODS/OSE to conduct a class to orient OND
colleagues to the approaches and methodologies employed by ODS/OSE
epidemiologists. The committee hopes that the leadership of the center will
initiate other such efforts and sustain them.
The goal of a more integrative, lifecycle approach to drug risk and
benefit is to have a preapproval process in which there is more active dis-
cussion about using clinical trial data to move drugs out quickly for high-
need populations while coupling the process with far greater attention to
a comprehensive plan for addressing uncertainties or emerging risks when
used after marketing in lower-need populations. Incorporating a lifecycle
approach to risk and benefit into various aspects of CDER organizational
culture and communicating that fact to all stakeholders could help bring
speed and safety into optimal balance.

The committee is aware that consumer advocates, legislators, and oth-

ers have asserted that the only solution to what, in their view, appear to
be intractable problems in CDER with regard to ensuring drug safety and
efficacy would be to create a separate center in FDA (or even a separate
agency) to work on postmarketing safety. The committee acknowledges the
legitimacy of the concerns that underlie such proposals, and it recognizes
that if the full complement of recommendations made in this report fails to
restore public trust in CDER’s (and FDA’s) credibility, competence, and ap-
pearance of independence, the secretary of DHHS and Congress may have
no alternative but to mandate substantial structural changes in the agency.
The committee believes, however, that if the recommendations made in this
report are implemented fully and change is sustained, other, more drastic
measures would be unnecessary. Safety and efficacy must always be in bal-
ance, and the ideal organizational solution is a team approach to assessing
both. Achieving a balanced approach to the assessment of risks and benefits
would be greatly complicated, or even compromised, if two separate orga-
nizations were working in isolation from one another. Premarket reviewers
develop extensive knowledge based on years of experience of monitoring
and reviewing the results of the premarket studies, and the system would
stand to lose a great deal if that knowledge were excluded from postmarket-
ing safety considerations.
External Environment
As described above, the environment that shapes the culture of CDER

and FDA is the product of societal expectations, legislative imperatives, and
economic forces. PDUFA represents a convergence of these factors.
Although PDUFA has led to increases in the speed of review and has
facilitated patient access to innovative drugs, it has also altered the environ-
ment in CDER, increased the pressure on reviewers to meet review dead-
lines, and perhaps even affected the agency’s relationship with sponsors. The
presence of PDUFA performance goals for review timeliness has increased
agency accountability to Congress and sponsors and has contributed to the
success of this reform in increasing review speed over time. However, the
existing PDUFA goals relate only to the speed of approval or non-approval
decisions and do not also reflect goals related to safety. If PDUFA is reautho-
rized in 2007, the committee believes that the goals on which FDA reports
to Congress need to include actionable performance goals for drug safety
activities in the premarket and postmarketing periods to ensure that impor-
tant agency functions receive sufficient resources. That would also help to
demonstrate that timeliness and safety are valued equally, just as risks and
benefits must be assessed together. There are now no explicit safety-related

goals that drive CDER’s work, whether or not associated with PDUFA
funding. Introducing new safety goals would be consistent with the lifecycle
approach to regulation.
The committee offers a series of suggested goals to assist CDER in
thinking about ways to couple accountability for timeliness and safety. Such
goals will ideally be quantifiable. Whether or not PDUFA is reauthorized
the committee believes it is important to measure and report on achieving
safety goals.
3.5: To restore appropriate balance between the FDA’s dual goals

of speeding access to innovative drugs and ensuring drug safety over
the product’s lifecycle, the committee recommends that Congress
should introduce specific safety-related performance goals in the
Prescription Drug User Fee Act IV in 2007.
Those goals, independent of funding source, could include the following

(organized topically):
Expertise in preapproval evaluation:

• Target participation rate for ODS/OSE staff involvement in drug
review teams: for priority original NDA and biologic license applica-
tion submissions 60 percent year 1, 70 percent year 2, 80 percent year
3, 90 percent year 4, and 100 percent year 5; for standard original
NDA and BLA submissions 40 percent year 1, 50 percent year 2, 60
percent year 3, 70 percent year 4, and 80 percent year 5.
• Report annually to Congress on the number of new molecular enti-
ties (NMEs) for which data were evaluated by external advisory
committees, and the proportion of all NME NDAs that that number
represents.
Monitoring of adverse drug reactions and Adverse Event Reporting System

(AERS):
• Prepare a summary analysis of the adverse drug reaction reports re-
ceived for a newly approved drug, which identifies any new risks not
previously identified, potential new risks, or known risks reported
in unusual number not previously identified within 18 months of
drug launch or after exposure of 10,000 persons, whichever is later.
Reports should be publicly available and posted on the agency’s Web
site.
• Conduct regular (biweekly) screening of the AERS database, espe-
cially 15-day reports, to identify new safety signals.
• Ensure that public access to AERS reports is updated every 6
months.

Postmarketing study commitments:

• Review the entire backlog of postmarketing commitments to deter-
mine which commitments require revision or should be eliminated
and report to Congress on these determinations. Of commitments
that remain, those without start dates should have start dates asso-
ciated with them to prevent perpetual “pending” status (12 months
from PDUFA IV initiation) (also see Chapter 5 for a discussion of
postmarketing, or Phase IV, commitments).
• Report completion rates (by company) for (i) postmarketing studies
requested prior to approval and (ii) postmarketing studies requested
when a drug is already on the market and the number of delin-
quent studies (past the original projected completion date) in each
category.
• Report on enforcement actions taken to ensure timely completion of
postmarketing study commitments (for commitments that are cur-
rently required, such as those associated with accelerated approval,
and for other commitments FDA will be able to require and enforce
after implementation of recommendations made in Chapter 5).
• Review and propose action, if warranted, on completed postmarket-
ing studies (within 60 days from submission of the study for actions
deemed urgent, 120 days for less urgent actions).
Postmarketing risk communication activities and risk management:

• In the annual PDUFA performance report to Congress, include the
timeliness of implementing regulatory actions10 (from the date of
the agency’s initial proposed action to the date of the actual labeling
change) and the number of such changes.
number of patient information sheets developed for new drugs and
the proportion of new drugs approved in that year for which patient
information sheets are developed. (The committee recognizes that
DrugWatch and other activities of the Drug Safety Oversight Board
are still under development. The final outcome could affect the rel-
evance and usefulness of this suggestion.)
• Review an applicant’s implementation of risk management plans and
make the report available on the agency’s Web site.
• Review and act on drug advertisements and promotional materials
submitted to the agency (within 90 days in year 1, 60 days in year 2,
30 days in year 3 and beyond).
10Including labeling changes, black boxes, and measures leading to drug withdrawal (see
Chapter 5 for discussion and recommendations on strengthening FDA’s authority).

Performance management:
• Convene an open forum 12–18 months before renewals of the
PDUFA to solicit public and industry comments on proposed and
existing safety goals for FDA.
status of meeting of all agency safety goals.
Discussion among all stakeholders is needed to consider what goals

would be the most valuable from a public health perspective.
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The Science of Safety
The deliberation and decisions of a science-based regulatory agency

depend on the quality of the scientific data that it obtains and reviews to
make valid scientific judgments. The science underlying drug development
is complex and multidisciplinary. As Chapter 2 describes briefly, the early
phases of drug development involve basic in vitro and in vivo research to
characterize general attributes of a drug. The staff of the Food and Drug
Administration (FDA) Center for Drug Evaluation and Research (CDER),
particularly in Office of New Drugs (OND) review divisions, works with
the industry sponsor of a drug to guide the design and the collection and
analysis of those data. The FDA Critical Path Initiative is designed to foster
the development of innovative scientific approaches to drug discovery and
development. (Critical Path also includes some effort to develop methods
for predicting safety problems better, for example, biomarkers of QT pro-
longation and indicators of liver toxicity; see Chapter 1.) This report of the
Committee on the Assessment of the US Drug Safety System focuses on data
generated and reviewed further along the development spectrum, so Critical
Path will not be addressed in detail, but the committee recognizes Critical
Path’s importance and the potential for better tools for the prediction and
early detection of the safety of pharmaceuticals as biomedical knowledge
increases (FDA, 2004). Enthusiastic as the committee is about the potential
of new biology and personalized medicine to contribute to the development
and use of safe drugs, the promise of the “right drug for the right person at
the right time” is not likely to be realized for most patients for some time.
There will always be a need for clinical trials and postmarket, population-
based studies to fully understand the risks and benefits associated with
105

drugs, especially to identify rare or unsuspected safety problems. Controlled

phase 4 studies will remain important for verifying that drugs approved on
the basis of limited exposures and surrogate end points actually have health
benefits and for assessing whether common adverse events can be attributed
to a drug when such events (such as heart attacks in older adults) emerge as
a potential safety signal. This chapter underscores the importance of gener-
ating strong science to support regulatory decision-making about the risks
and benefits associated with drugs and the importance of ensuring that the
decisions made throughout a drug’s lifecycle are credible and transparent.
GENERATING THE SCIENCE
Understanding Risk and Benefit for Approval Decisions

As has been described in Chapter 2, a New Drug Application (NDA)
and the reviews of an NDA by CDER staff contain thousands of pages of in-
formation about the effects of a drug. CDER clinical reviewers are expertly
trained to analyze the efficacy and safety data from clinical trials. Individual
case reports of adverse events from the trials are reviewed, as are compari-
sons of event rates of many safety outcomes in the overall product database,
including those in uncontrolled safety studies. The reviewers also consider
the statistical methods used by the company to generate the results. CDER
has issued many guidances and documents of policies and procedures outlin-
ing the best ways to review and analyze such data (DHHS et al., 2005; FDA,
2005c). Clinical trials are designed to test hypotheses that are the agreed-
on bases for determining efficacy. Trials designed to test hypotheses about
serious safety outcomes would in most cases require many more subjects
than are needed for an efficacy endpoint. For some conditions, the efficacy
outcomes may be surrogate endpoints, which are expected to capture the
information about efficacy but are usually not informative about safety.
Safety information can emerge from clinical trials, but rare events may
not surface at all; if they do, it is at a rate so low that one cannot distinguish
a drug-caused event from one expected by chance (background incidence).
Safety information is usually limited to reports of common adverse events,
the relation of which to drug exposure can be assessed by comparing rates
between study treatment groups, or adverse events already predicted by re-
sults of animal studies or in connection with other drugs in the same class.
Safety information also includes abnormalities in clinical laboratory test
values seen during preapproval trials that may portend occasional clinically
significant events. That set of suspected adverse events serves as a starting
point for decisions about postmarket surveillance and drug safety research.
The safety profile of a new molecular entity (NME) is especially uncertain,
because of a lack of information on similar drugs already on the market.

THE SCIENCE OF SAFETY 107
Murglitazar, a drug for diabetes that activates both alpha- and gamma-
peroxisome proliferator-activated receptors, was reviewed by FDA for ap-
proval during the committee’s work. In the preapproval trials, compared
with the other arms of the trials (some compared the drug with a placebo,
others with another diabetes medicine), murglitazar improved sensitivity
to insulin and the control of blood lipids in patients with type 2 diabetes.
Those efficacy outcomes are examples of surrogate endpoints because they
are expected to predict the occurrence of cardiovascular events. In the
same preapproval trials, however, patients randomized to murglitazar had
a significantly higher incidence of the combined outcomes of death, heart
attack, stroke, and heart failure. The reason for the discrepancy between
surrogate endpoints and health outcomes is not clear, but the case of mur-
glitazar illustrates the importance of verifying the assumed health benefits
of new drugs and of conducting more complete risk-benefit analyses (Nissen
et al., 2005).
As described in Chapters 2 and 3, OND clinical reviewers are primarily
responsible for assessing the safety information in an NDA, and interactions
and involvement of the Office of Drug Safety/Office of Surveillance and
Epidemiology (ODS/OSE) staff vary among OND offices. A recent time-
accounting exercise by CDER reports that OND devotes 51 percent of total
scientific and technical staff effort on safety-related activities (FDA, 2005a).
Despite that large investment of time and effort, the safety profile of a drug
at the time of NDA review is necessarily uncertain at the time of approval.
The only certainty at the time of approval is that the CDER official who
signed the approval letter has not identified safety problems that in his or
her best judgment outweigh the potential benefit of the drug for the specific
indication and population studied. However, to expect that premarket stud-
ies or FDA review of these studies can reveal all the information about the
risks and benefits of new drugs that is needed to make optimal treatment
decisions would occasion unreasonable delay in approval.
Reducing Uncertainty About Risk and Benefit After Approval

As described in other sections of this report, important new information
about a drug’s effectiveness accumulates after approval, although effective-
ness is extremely diffcult to assess outside the context of a randomized trial.
The committee has chosen to describe the major components essential to as-
In May 2006, CDER renamed the Office of Drug Safety (ODS) the Office of Surveillance
and Epidemiology (OSE). The committee will refer to this office as ODS/OSE in the report in
recognition that some statements refer to actions of the office in the past and some statements
refer to the present.
Efficacy refers to effects in controlled clinical trials; effectiveness refers to effects in the
“real world.”

sessment of drug safety after approval as the generation of hypotheses based

on early safety signals, the strengthening of safety signals, the conduct of
confirmatory studies to identify and quantify new or hypothesized risks and
benefits, the evaluation of risk management programs to minimize known
safety risks, and the continuing evaluation of risks and benefits in light of
new risk or new benefit information to ensure that the known benefits of a
drug continue to outweigh the known risks. The committee concludes that
although CDER is involved in a variety of activities to generate and assess
postmarket safety information, the current approach is not as comprehen-
sive and systematic as is needed to serve drug safety and public health objec-
tives optimally. The committee offers specific recommendations to CDER
and other federal departments and agencies for improving postapproval
assessment of drug-related risks and benefits.
Signal Generation
Although some safety signals are generated in laboratory tests and clini-
cal trials conducted in the preapproval setting or from known or suspected
biologic actions of a drug, the primary method by which FDA documents
new adverse events in the postmarket setting is monitoring of suspected ad-
verse drug reaction reports entered into the Adverse Event Reporting System
(AERS). AERS combines the voluntary adverse drug reaction reports from
MedWatch, such as direct reports from healthcare practitioners and con-
sumers, and the required reports from manufacturers—15-day expedited re-
ports of serious and unexpected adverse events and manufacturer periodic
reports. The information provided by this part-voluntary, part-mandatory
system of reporting forms the basis of detection of many safety signals and
has been useful in identifying rare adverse events.
Spontaneous AERSs have many limitations, but they offer the possibil-
ity of identifying rare serious adverse events in a timely manner among all
persons across the entire region to which the system applies. For example, if
there is a one-in-a-million serious adverse event applicable to those exposed
to a drug used in 10 million people per year in the United States, it might
never be observed in a database of several hundred thousand, or even several
million people in which the number exposed to the drug might be only a
few thousand per year. But in the entire United States it is not so unlikely
that at least one such event would get reported. Even a small number of
reports of events that are commonly caused by drug exposure, such as liver
or kidney failure, aplastic anemia, anaphylaxis, Stevens-Johnson syndrome,
A serious adverse event is any untoward medical occurrence that at any dose: results in
death, is life-threatening, requires or prolongs inpatient hospitalization, results in persistent or

significant disability or incapacity, is a congenital anomaly or birth defect (CFR 312.32).

and so on, can constitute an important safety signal. Spontaneous reporting

is subject to certain limitations, including underreporting, the influence of
bias in reporting, lack of denominator data, and difficulties in attribution
of association between reported event and drug exposure.
Little has been done to optimize the usage of AERS for drug safety sig-
nal detection until recently. The work of DuMouchel and others raised the
real possibility of doing automated searches of AERS to identify possible
associations worthy of further followup. These “data mining” techniques
greatly increase the value of AERS data, and that of other spontaneous re-
porting systems. Developing more rigorous systems in which to investigate
AERS signals or any other possible risks of interest is warranted and long
overdue; such systems have the potential to improve the ability to develop
safety information in a more rapid and more reliable manner. The Centers
for Education and Research on Therapeutics (CERTs) are assessing the po-
tential use of health care databases for enhanced identification of adverse
drug events. But the addition of new tools such as the use of health care
databases does not mean we should abandon the old, especially now that
we have methods to substantially enhance the value of these older tools.
In 2004, FDA received 422,889 reports of suspected drug-related
adverse events. Of those reports, 21,493 were MedWatch reports directly
from individuals (about 15 percent of which came directly from consum-
ers), 162,107 were manufacturer 15-day (expedited) reports, 89,960 were
reports of serious events included in manufacturer periodic reports, and
149,329 were reports of other events included in manufacturer periodic
reports. As described in Chapter 2, safety evaluators in ODS/OSE review
case reports in their drug-class portfolios. That is necessarily very time-
consuming. Electronic submission of adverse event (AE) reports makes the
system more efficient and timely, although it is reported that only half of
the AE reports are submitted electronically, so the AERS contractor must
spend time in performing data entry before the information can be reviewed
by the safety evaluators.
A safety evaluator receives about 650 electronic reports per month.
Review of AE reports can sometimes identify rare or unusual events that
require additional research to understand. The following are some drugs for
which AEs were identified through AERS: terfenadine (torsade de pointes
and sudden death), cisapride (torsade de pointes and sudden death), tro-
glitazone (hepatic failure), infliximab (tuberculosis and opportunistic infec-
tions), and cerivastatin (rhabdomyolysis) (Wysowski and Swartz, 2005).
Statistical approaches available for the analysis and display of AERS data
(such as the WebVDME program) have received only limited use by CDER
until recently. CDER staff have recently described how the use of a Bayesian
statistical analysis would have confirmed the cerivastatin, rhabdomyolysis,
and renal failure association after 6 months of postapproval use if it had

been available (Szarfman et al., 2002). Other systematic methods of screen-

ing for AEs have also received little attention, although their use appears
to be increasing. The committee is aware of the criticisms of AERS, but the
committee believes that the planned update known as AERS-2 will useful.
The committee supports a focused improvement in how CDER uses passive-
surveillance reports as a tool in drug safety research.
4.1: The committee recommends that in order to improve the gen-

eration of new safety signals and hypotheses, CDER (a) conduct a
systematic, scientific review of the AERS system, (b) identify and
implement changes in key factors that could lead to a more efficient
system, and (c) systematically implement statistical-surveillance
methods on a regular and routine basis for the automated genera-
tion of new safety signals.
The committee does not intend that review of AE reports, whether sub-
mitted by manufacturers as mandatory under federal regulation or submit-
ted by patients or their providers through the MedWatch program, be the
primary tool used by CDER for postmarket safety analysis. The committee
does not support making AE reporting mandatory. Enforcing mandatory
reporting is difficult and the committee’s goal is to have better reporting
and better use of what is reported, not to increase the workload of CDER
safety evaluators with unhelpful information. The passive reporting system
in place today is capable of, and has made, important contributions, and
the committee hopes that CDER will work to make the current system more
efficient. In the next section, the committee offers recommendations for
tools that will supplement and complement the AERS system and provide
better data for regulatory and public health purposes.
Signal Strengthening and Testing
The development and implementation of a lifecycle approach to the

evaluation of the risks and benefits related to drugs will require expanded
efforts in signal strengthening and signal testing in the postmarket setting.
Once safety evaluators in ODS/OSE or clinical reviewers see sufficient num-
bers of similar case reports, they have to decide whether apparent signals are
real—that is indicative of a problem—or just “noise” in the system. That
determination should begin with the application of available tools, such as
sector maps and empirical Bayes reporting ratios for analyzing spontane-
The committee is aware that CDER is beginning to undertake an information-technology
upgrade of AERS.
Such as data sources, coding, quantity, quality of reports, and best use of CDER staff.

ous reports and should continue with more active methods of evaluating
signals.
Sometimes, the need for signal-strengthening studies is anticipated at
the time of approval. Just before approval, CDER negotiates about phase
4 studies that the company commits to conducting. Chapter 2 includes
information about the number of those studies that are not completed.
An exception to the inability of CDER to compel the studies is the case in
which a drug is approved under accelerated approval. Postmarketing stud-
ies range from simple pharmacokinetic studies through analysis of data in
administrative databases to controlled trials. The current approach, leaving
the negotiations of plans for postmarket studies to the late stages of the pre-
approval process, is not optimal and may lead to studies that are not well
designed. That is one of the reasons why a large proportion of postmarket
commitments are not started or completed. Another factor that could
contribute to suboptimal design is uncertainty of OND clinical reviewers
about the types and designs of postmarket studies that might be developed,
particularly observational studies. It is unusual for CDER to bring in outside
experts for independent review and advice about the hypotheses and design
of phase 4 studies committed to at the time of approval, but such advice
might be useful. As described in Chapter 2, input from advisory committees
is often not sought because of committee meeting schedules.
A strong postmarket safety system requires a wide array of data resourc-
es that permit continuing evaluations. Some may be directed at tracking
patterns of drug use, the indications for the use of a drug in the population,
and a general description of the types and frequencies of various AEs. Others
may be directed at signal generation. For instance, as electronic medical-
records databases are further developed, it may be possible to incorporate
real-time reporting of AEs that can be made available to FDA for analysis.
Such an effort would require considerable development.
Signals or hypotheses about safety issues may arise from other sources,
including known or suspected biologic drug effects that become evident
through animal and human studies. Once a potential signal is identified,
followup studies are likely to involve the use of a variety of study designs
and data sources, including large electronic administrative databases. ODS/
OSE has four task-order contracts for access to administrative databases
for epidemiologic research. The contractor sites are the HMO Research
Network, Ingenix Inc., the Kaiser Foundation Research Institute, and Van-
derbilt University (Seligman, 2005). Cumulatively, those organizations cover
23.5 million people, and each has characteristics that make it particularly
useful. For example, the Vanderbilt site uses Medicaid data from Tennessee
and Washington and thereby obtains information about high-risk and eth-
This program had previously been funded through a cooperative agreement mechanism.

nically diverse populations. The Ingenix site has access to some laboratory
data in addition to claims data, and the HMO Research Network and the
Kaiser Foundation Research Institute sites have access to electronic medical
records. Study designs for the contracted studies often are presented to the
Drug Safety and Risk Management Advisory Committee or involve other
outside experts through the special government employee mechanism for
review and comment as a form of scientific peer review.
The funding for the cooperative agreement program is severely limited
and the program has always been small. In 1985, the funding level was $1.2
million; since then, resources have varied. Despite inflation in the interim,
funding for FDA drug safety cooperative agreements reached a low of
$900,000 in 2000 (personal communication, Gerald Dal Pan, FDA, March
30, 2006). In fiscal year (FY) 2006, funding for FDA drug safety contracts
totals only $1.6 million, and it is scheduled to decrease to $900,000 in
FY 2007. According to an ODS annual report, the contract program in
2004 supported five feasibility studies and three in-depth studies, but in
FY 2006 the program will have sponsored feasibility studies for two drug
safety questions and will not have sufficient funds to execute one high-
priority in-depth study fully—on the cardiovascular risks posed by drugs
prescribed for attention deficit hyperactivity disorder (ADHD) (IOM Staff
Notes, 2005–2006). In contrast, a similar program funded by the Centers
for Disease Control and Prevention (CDC) to study safety problems associ-
ated with vaccines, the Vaccine Safety Datalink (VSD), included data on
more than 7 million people covered by eight managed-care organizations.
CDC supported the VSD with $13 million and eight full-time staff persons
in FY 2004 (Davis, 2004).
FDA also works with the CERTs that have access to large healthcare
databases, including the HMO Research Network and the Department of
Veterans Affairs (VA). CDER has internal access to the General Practice Re-
search Database (GPRD) and to proprietary databases that house exten-
sive information on drug use. Access to the GPRD was expected to provide
valuable information to CDER for drug safety purposes, but ODS/OSE has
struggled to get sufficient computer resources and staff trained to use it. Four
full-time safety evaluators now work with those databases, and two staff
epidemiologists work part-time with them in their research.10 CDER staff
presented their first findings from the GPRD at the 2006 summer meeting
of the International Society of Pharmacoepidemiology.
A feasibility study involves preliminary assessments of whether a database contains suf-
ficient exposures or outcomes in appropriate populations to answer the study question.
A computerized database of longitudinal medical records from primary care practices in the
United Kingdom and a source of data for many epidemiologic studies around the world.
Verispan, LLC; IMS Health; and Premier.
10Personal Communication, G. Dal Pan, FDA (ODS/OSE), 2006.

VA serves an enrolled population of 7.7 million veterans, their family

members, and survivors through its more than 1,300 sites of care, includ-
ing 154 medical centers. The presence of automated databases and a pre-
scription drug benefit makes VA a promising setting for postmarket drug
studies. There are some examples of the use of data from the VA system
for studies of the prevalence of AEs (Nebeker et al., 2005) and case-control
studies of possible adverse effects of drugs (Shannon et al., 2005). VA and
CDER would like to work together to use this resource more broadly, but
resource limitations prevent more extensive collaboration. VA populations
are included in the research of a few of the CERTs (CERTS, 2006; UI Health
Care News, 2006).
There is near-unanimous agreement that the Medicare Modernization
Act and the Medicare Part D benefit offer potential new resources for post-
marketing drug studies. As of January 2006, an estimated 43 million people
on Medicare were eligible to sign up for prescription drug coverage through
Part D plans, and the Department of Health and Human Services (DHHS)
indicates that 19.7 million beneficiaries were enrolled as of April, 2006
(Kaiser Family Foundation, 2006). Because the elderly are frequent users of
multiple medications for concomitant diseases, data from Medicare Part D
could play an important role in postmarket drug studies, particularly given
the opportunity to create linkages among pharmacy, outpatient, inpatient,
physician office, and emergency-department claims. FDA has endorsed a
proposal, lacking in detail, to establish a postmarketing surveillance system
for prescription drugs that would use billing data and health care infor-
mation collected from Medicare beneficiaries (Kaiser Family Foundation,
2005). Through the Agency for Healthcare Research and Quality (AHRQ)
Developing Evidence to Inform Decisions about Effectiveness (DEcIDE)
Network, investigators are developing a methodologic toolbox and data-
analytic framework for using population-based claims and administrative
data sources in pharmacoepidemiologic and pharmacovigilance research
(DHHS and AHRQ, 2006).
This kind of research is labor-intensive, and specialized knowledge is
required to use some of the databases. A small number of ODS/OSE epide-
miologists and safety evaluators are trained to use the databases directly or
to collaborate with other researchers to design and analyze data, and they
have limited time to conduct research because of their other responsibilities
(such as responding to OND consults, working to develop needed CDER
guidances, and preparing for meetings).
The advantages of research using health care databases include the abil-
ity to conduct studies of uncommon diseases or understudied populations
with respect to drug exposures, minimization of study costs, reduction in
the time required to complete a study, and the opportunity to study large
numbers of patients. Those systems can also provide valuable information

on the background incidence of AEs, which is helpful in understanding the

significance of findings in passive-surveillance systems. The disadvantages in-
clude missing data and misclassification of key data on outcomes (Hripcsak
et al., 2003), drug use, or potential confounding factors. Information on
severity of illness or functional status is often uniformly missing (Jackson
et al., 2006) and selection bias cannot be prevented from influencing results.
The large samples in administrative databases can provide considerable
power to assess associations; however, precise but biased estimates of risk
are not generally useful. Other disadvantages are difficulties in gaining ac-
cess to primary medical records (and access to patients themselves), either
entirely or on more than just a sample basis; dependence on diagnostic
coding systems, which can be problematic for some conditions or topics;
and drug-formulary restrictions in some health plans that limit the ability
to study newer drugs if they are not on the formulary. Finally, much of the
useful clinical information, such as descriptions of adverse reactions, exists
only in narrative form, which makes automated analysis difficult (Jollis
et al., 1993). There are strategies for correcting for some of the limitations
of the databases (such as chart review to find missing data or to improve
the accuracy of information), but they are sometimes resource-intensive.
Consideration must be given to the strengths and limitations of the data
in setting priorities within the program and between research methods for
addressing a specific safety problem.
In some instances, active surveillance to generate safety signals and re-
solve other knowledge gaps is useful. Active surveillance is the regular, peri-
odic collection of case reports from health care providers or facilities. CDER
has been involved in developing a limited number of active-surveillance
strategies. One example is an emergency room-based surveillance project
for drug-induced injury, the National Electronic Injury Surveillance System–
Cooperative Drug Adverse Event Surveillance System (NEISS–CADES),
jointly funded by the Consumer Product Safety Commission, CDC, and
FDA. FDA recently issued a request for information that stated its interest in
this regard. In addition, FDA has cosponsored pilot development of a drug-
based surveillance system that explores the feasibility of using data-mining
techniques to identify safety signals in automated claims databases (DHHS,
2005). NEISS-CADES was used very recently to document AEs associated
with stimulant medications used for ADHD (Cohen et al., 2006).
4.2: The committee recommends that in order to facilitate the for-

mulation and testing of drug safety hypotheses, CDER (a) increase
their intramural and extramural programs that access and study
data from large automated healthcare databases and (b) include in
these programs studies on drug utilization patterns and background
incidence rates for adverse events of interest, and (c) develop and

implement active surveillance of specific drugs and diseases as

needed in a variety of settings.
Other federal partners in the drug safety system (VA and the Centers for
Medicare and Medicaid Services, CMS, in particular) also use automated
databases and should work with CDER, as appropriate, to accomplish the
goal of improved formulation and testing of drug safety hypotheses for the
entire drug safety system. As will be described in Chapter 7, CDER and its
federal partners in the drug safety system will need increased resources to
accomplish these goals.
Confirmatory Studies
Passive surveillance, epidemiologic research with administrative da-

tabases, and active surveillance can be used to answer many drug safety
questions. When they do not provide definitive answers, they can sometimes
provide guidance for the development of further studies or provide sufficient
information to narrow the uncertainty about drug-related risks and benefits
and guide regulatory actions and the decisions of patients and providers.
In some instances, full-scale observational studies or clinical trials will be
required to answer key questions, particularly if the outcome of interest is
common in the patients taking a drug. Such studies are often expensive and
time-consuming, but they provide valuable information that less rigorous
studies cannot provide. For example, the Women’s Health Initiative (WHI)
and the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart
Attack Trial (ALLHAT) cost an estimated $725 million and $125 million,
respectively, but provided valuable evidence about efficacy and safety.
Although $125 million seems like a lot of money, 28.4 percent of the
adult population, or about 65 million men and women, of the United States
have high blood pressure (Fields et al., 2004), and more than half of them
are taking medications for it (Hajjar and Kotchen, 2003). The annual costs
of two of the blood-pressure medications used in ALLHAT are about $547
for amlodipine (a calcium-channel blocker) and $83 for chlorthalidone (a
low-dose diuretic) (The Medical Letter, 2004). Demonstration that low-cost
and older drugs, such as diuretics, are the most effective first-line treatment
for high blood pressure can improve health outcomes and save money.
ALLHAT also helped to resolve uncertainty about the safety profile of the
calcium-channel blockers.
There is no realistic mechanism to ensure that important phase 4 clini-
cal trials are done. As discussed in Chapter 2, some phase 4 studies to be
conducted by the drug sponsor are agreed on at the time of drug approval,
but for various reasons, many of those studies are never completed. FDA has
no authority to compel the completion of these studies, and industry could

be reluctant to conduct them because of high costs and the possibility that
unfavorable results would negatively influence market share.
A significant impediment to the successful completion of studies is that
they are typically negotiated between CDER and the industry very late in
the approval process. The study designs can be inadequate, and there is
little opportunity given time constraints imposed by the Prescription Drug
User Fee Act (PDUFA), for CDER to bring in outside experts when they are
needed to help with study design. Experts who are in the pool of potential
special government employees (including advisory committee members) can
be consulted, but they must be screened for conflicts of interest, and only
one can be brought in at a time to comply with the Federal Advisory Com-
mittee Act. Although there may be legitimate reasons for abandoning some
of the phase 4 study commitments, many could be useful, especially with
study-design improvement.
Once a drug is approved, unless the industry sponsor is looking for a
new indication for the drug, CDER has no leverage to require further stud-
ies by the company. Pharmaceutical companies continue to conduct clinical
trials of their drugs, and there is an emerging recognition that these are
often marketing-driven and their designs may be inadequate for any reliable
assessment of safety or efficacy (Psaty et al., 2006), may underreport AEs,
may lead to selective publication of favorable results and non-publication
of studies whose findings are unfavorable for marketing (Psaty and Rennie,
2006), and therefore can be misleading. The concept of these “seeding” tri-
als, performed primarily for marketing purposes, is not new (Kessler et al.,
1994).
CDER does not have the resources to fund large randomized clinical
trials, nor was it ever intended to do so. The drug safety system is currently
dependent on the industry, the National Institutes of Health (NIH), or foun-
dations to fund such studies. Other groups have a strong interest in reducing
the uncertainty about therapeutic risks and benefits—health care payers, for
example—but they have not typically conducted large and expensive phase
4 trials. No entity is responsible for helping to set priorities among the drug
safety and drug efficacy questions that need to be examined, particularly
with resource-intensive controlled trials. Some studies are necessary for an-
swering questions for regulatory purposes (such as whether risks outweigh
benefits and what regulatory action should be taken); others are important
for public health purposes and are not likely to be funded by industry (such
as head-to-head trials of drugs approved for the same indication).
The potential cost of large safety trials has been a concern for many. A
model for “large, simple trials” was established in the United Kingdom in
the 1970s; a series of increasingly large randomized trials was conducted
to examine regimens for treatments to prevent cardiovascular mortality in

those at elevated risk. Those trials were conducted with very modest bud-
gets. Although the costing of trials in the United Kingdom and the United
States is admittedly very different due to differences in the way health care
and biomedical research are supported in the two countries, there may be
ways to conduct trials in the United States with substantially smaller budgets
than has been assumed. The increasing computerization of medical data and
move toward electronic medical records may facilitate the implementation
of more efficient trials with fewer personnel needs. Research into methods
for conducting simpler, less expensive trials that might be suitable for an-
swering straightforward but important safety questions is warranted, and
represents a logical area for FDA scientific involvement, even leadership.
4.3: The committee recommends that the Secretary of HHS, work-

ing with the Secretaries of Veterans Affairs and Defense, develop a
public-private partnership with drug sponsors, public and private
insurers, for-profit and not-for-profit health care provider organi-
zations, consumer groups, and large pharmaceutical companies to
prioritize, plan, and organize funding for confirmatory drug safety
and efficacy studies of public health importance. Congress should
capitalize the public share of this partnership.
The program for confirmatory studies should focus on the conduct

of large, long-term phase 4 clinical trials to evaluate the health risks and
benefits associated with chronic-disease medications approved on the basis
of short-term trials of surrogate endpoints—such as blood pressure and
lipid and hemoglobin A1c concentrations—and on comparative safety and
effectiveness studies. The public-private partnership could also consider
studies of cost-effectiveness, particularly comparative cost-effectiveness,
which is unlikely to be studied by industry and would be very important
for those members of the public-private partnership who are insurers and
provider organizations, including the VA, CMS, and Department of Defense
(DoD). The randomized clinical trial is the optimal method of assessing
the efficacy and safety of a drug therapy, but there are other approaches,
including analyses of physical or electronic medical records, patients, and
specimens identified in the large automated databases and analyses of data
from observational studies.
DHHS agencies with an interest in drug safety include FDA, NIH,
AHRQ, CDC, and CMS. VA already partners in a limited way with FDA in
some drug safety studies, and both agencies express an interest in expanding
that collaboration. With a system of 7.7 million veterans and over 100 mil-
lion prescriptions filled every year and with excellent electronic records, VA
would provide valuable data as well as insight and expertise to this partner-

ship. The committee is not aware of any collaborations with DoD on such
studies,11 but DoD provides health care coverage to over 9 million persons
and has excellent epidemiologic research capacity, easily accessible research
subjects, and a national interest in the safest and most effective use of drugs
for troop readiness and cost containment for the largest health care system
in the country. That is why the committee included DoD in the partnership.
NIH has supported many important such trials, and the committee expects
it will continue to do so. Each agency in the collaboration will need staff
dedicated to this work in addition to information-technology upgrades and
administrative support.
Discussions about needed confirmatory studies should include regula-
tory findings and related advisory committee input, should address major
study-design issues, and should lead to studies that supplement and comple-
ment those being done by industry sponsors as part of their postmarket
study commitments. The committee urges industry to use the expertise of the
proposed public-private partnership for comment on the design of studies
and for oversight of study conduct and analysis of results. Proposals for all
confirmatory drug safety studies, whether funded or conducted by public
or private entities, should be subject to a peer-review process modeled after
NIH study sections to ensure scientific excellence.
An important outcome of the partnership should be that federal agen-
cies provide FDA access to all administrative databases12 (under conditions
consistent with the protection of patient privacy) managed by the federal
government for purposes related to postmarketing surveillance, safety moni-
toring and analysis, and risk-benefit assessment of approved drugs.
Funding for the studies planned by the partnership would come from
different sources, including congressional appropriations, depending on
the questions to be addressed. Some studies planned under this partnership
would have been conducted absent the partnership; therefore, the resources
needed are not all additional costs to the system. It is hoped that the partner-
ship would help prioritize questions and advise on important study design
issues. The partnership might also facilitate collaborations that otherwise
would not occur. The committee believes that industry bears the respon-
sibility for paying for clinical trials and other observational studies which
support a product’s approval and its safe and effective use (e.g., specific
11DoD and other agencies have collaborated in planning and analyzing complementary stud-
ies of the safety of the smallpox and anthrax vaccines.
12This could be accomplished by training CDER staff to use the databases directly or to work
with staff in the other agencies. In either arrangement, new staff will be needed to implement
this recommendation. Access to the databases could be obtained through an interagency task
force (either existing or to be created) including representatives of FDA, representatives of
federal agencies that manage medical databases, and other members to coordinate and ensure
effective use by FDA of such medical databases for postmarketing drug safety.

postmarket study commitments) and that both government and industry, in

collaboration with others, bear the responsibility for funding other clinical
trials or observational studies performed for broader public health objec-
tives rather than specific regulatory purposes. Industry also has a social
responsibility to make sure that its products are safe and effective, so it
should contribute to these trials of public health importance. The secretary
of DHHS should provide funding for the administrative management of the
partnership, but funds for the research will need to come from a variety of
sources. CDER will need support from the FDA commissioner and from
the secretary of DHHS to use the information from the studies for the best
regulatory policy-making. The committee understands that priority-setting
and collaboration will not be easy, but they are necessary for advances in
drug safety.
Risk Minimization Action Plans

As described above, some drug safety problems are suspected, some are
unknown and unsuspected, and others are known at the time of approval.
Risk management is an iterative process that encompasses the assessment
of risks and benefits, the minimization of risks, and the maximization of
benefits. The committee views with concern the CDER statement that the
“cornerstone” of risk management encompasses “efforts to make FDA-
approved professional labeling clearer, more concise, and better focused
on information of clinical relevance” (FDA, 2005b). There is widespread
acknowledgment that product labeling has not been a very effective means
of communication to prescribers about risk management.
PDUFA III required FDA to issue guidances to industry on risk man-
agement. The preceding sections of this chapter describe tools to assess and
clarify drug risks and benefits. Risk minimization is the effort to minimize
risks already identified. Risk minimization action plans (RiskMAPs) consti-
tute a relatively new approach to minimizing known risks of a drug beyond
the standard industry responsibilities related to routine risks, such as label-
ing and reporting of AEs. According to the guidance entitled “Guidance
for Industry, Development and Use of Risk Minimization Action Plans,”
“RiskMAP means a strategic safety program designed to meet specific goals
and objectives in minimizing known risks of a product while preserving its
benefits. A RiskMAP targets one or more safety-related health outcomes or
goals and uses one or more tools to achieve those goals” (FDA, 2005b). The
guidance describes the following possible RiskMAP tools:
• Targeted education and outreach to communicate risks and appropri-

ate safety behaviors to healthcare practitioners or patients.

• Reminder systems, processes, or forms to foster reduced-risk pre-

scribing and use.
• Performance-linked access systems that guide prescribing, dispensing,
and use to target the population and conditions of use most likely to
confer benefits and to minimize particular risks.
NDAs for NMEs are required to include RiskMAPs, but at the time of
approval most non-NMEs will not need RiskMAPs. Known risks can be ad-
dressed through standard industry and CDER activities. Information about
possible risks can be sufficiently uncertain that appropriate minimization
strategies are not obvious.
RiskMAPs can also be developed or modified after marketing. Every
RiskMAP should be viewed as a “living document” that evolves throughout
the lifecycle of a drug. One of the best examples is the case of isotretinoin, a
teratogenic drug indicated for severe cystic acne. The risk minimization ac-
tivities for this drug have increased in complexity. The Pregnancy Prevention
Program (PPP) was established in 1988 in an attempt to prevent exposure of
pregnant women to isotretinoin. The PPP asked female users of isotretinoin
to enroll voluntarily in a survey administered by Boston University’s Sloane
Epidemiology Unit and enrolled 45 percent of women of reproductive age
who were using the drug. Of these women, 36 percent did not have any type
of pregnancy test before beginning treatment, and about 900 pregnancies
occurred among enrollees during 1989–1998 (No Author, 2000). A new
program, SMART (System to Manage Accutane Related Teratogenicity),
was implemented in 2002 (Levine A, 2002; Honein et al., 2004). SMART
retained the voluntary registration of PPP and
• Added a requirement for two negative pregnancy tests before the

first prescription with the second pregnancy test occurring during
menses.
• Added qualification stickers on each prescription to confirm that the
patient had agreed to use contraception and had signed an informed
consent about the teratogenic risks posed by isotretinoin and to
verify that the physician had confirmed the negative pregnancy tests
and had counseled the patient about participation in the voluntary
followup survey.
• Added a requirement that prescriptions not be filled without a quali-
fication sticker.
• Added a requirement that prescriptions not be filled more than 7 days
later than the qualification date on the sticker.
• Added a restriction that limited all prescriptions to a 30-day
supply.
• Disallowed automatic refills and telephoned-in prescriptions.

• Increased incentives for survey participation.
The first-year evaluation of SMART found that 127 pregnancies were

reported among isotretinoin users in the year before SMART (April 1, 2001,
to March 31, 2002) and 120 during SMART’s first year (April 1, 2002, to
March 31, 2003) (Avigan and DalPan, 2004; Pitts and Karwoski, 2004;
Ackermann Shiff et al., 2006).
The ineffectiveness of SMART led to a more aggressive approach.
iPLEDGE, the risk management program instituted in March 2006, drew
praise for its comprehensiveness but criticism that the complicated respon-
sibilities for patients, prescribing physicians, and dispensing pharmacists
would discourage use. Key components of iPLEDGE are registration of
patients and pharmacists, documentation by female patients of child-bearing
potential of two forms of contraception and a laboratory-confirmed nega-
tive pregnancy test, verification by the pharmacist that the prescription is
valid, and distribution of a medication guide.
RiskMAPs are a fairly new development, and an FDA guidance ac-
knowledges the need for evaluation of plan performance (FDA, 2005b).
PDUFA III gave ODS/OSE a role in the review and evaluation of risk man-
agement plans. The PDUFA III goals call for ODS/OSE participation in
pre-NDA meetings and pre-biologic license application meetings to discuss
preliminary risk management plans and proposed observational studies and,
in the period 2–3 years after approval, to evaluate risk management plans
after implementation.
4.4: The committee recommends that CDER assure the perfor-

mance of timely and scientifically-valid evaluations (whether done
internally or by industry sponsors) of Risk Minimization Action
Plans (RiskMAPs). This review should include determining whether
an individual RiskMAP is effective and overall evaluations of
the strategies used and the processes of CDER staff and industry
sponsors for planning and implementing RiskMaps. Evaluations
should consider burdens and consequences in addition to design
and effectiveness.
Risk-Benefit Analyses Throughout the Lifecycle

The regulatory decision to approve a drug requires the determination
that the benefits of the drug outweigh the risks associated with it when used
for the indication for which the drug is approved. That is, the drug must
demonstrate a favorable risk-benefit profile. As a country we have chosen
to place a significant degree of decision-making about the availability and
potential use of medicines in the hands of a science-based regulatory body.

The FDA is the first gatekeeper regarding access to drugs in exercising ap-
proval authority. Some drugs, perhaps even many, will not and should not
be permitted to be used by patients who expect their medicines to be safe
and effective. Some believe that drugs should be made much more freely
available on the market for anyone who wishes to use them, particularly
if the patient has a fatal disease for which they are willing to take the
chance that a drug will have little benefit and possibly many serious risks
(Burroughs and Walker, 2006). For many of these situations, accelerated
approval was developed as a mechanism to make selected promising drugs
available early in their evaluation.13 However, it is widely accepted that the
FDA has the authority to determine whether the risk-benefit profile for a
drug is appropriate to release the drug on the market. Whether the “bar” for
approval is too high or too low for particular drugs has not been the focus
of this committee’s efforts. In practice, once a drug is approved, health care
providers and patients make many decisions about use of a drug. In this
section we discuss ways that the regulator can make those decisions easier,
by being more explicit about what is known and not known about the sum
total of a drug’s benefits and its risks.
As described elsewhere in this report, there are many uncertainties at
the time of approval. Eliminating all those uncertainties prior to approval
would require an unreasonable number of premarketing studies and would
have serious implications not only for pharmaceutical companies in terms of
research and development but also for patients awaiting new and important
medicines. What regulators and drug sponsors know about the drug at ap-
proval will change over time. Some of that new information will pertain to
the benefits of potential new indications for the drug and other new informa-
tion will pertain to the risks or adverse effects of the drug. For example, the
results of additional studies completed during a drug’s postapproval period
can alter our understanding and perception of the risk-benefit profile and
result in new actions on the part of FDA, clinicians, and the public.
FDA reviews a drug for benefits and risks from the perspective of its
intended use (the indication in a population), but in most instances, the drug
will not have been evaluated for so-called off-label use. Spontaneous reports
of adverse events may indicate a potential safety problem and warrant a
safety study. Safety and effectiveness data from studies on uses other than
the approved indication are gathered if the sponsoring company is studying
the drug in clinical trials for a supplemental NDA for a new indication or
if sufficient off-label use occurs. Formal studies of safety and/or effective-
ness can also be undertaken. There is a “rolling” or incremental increase
in information about the risk-benefit of most drugs after licensure and the
13Other mechanisms to increase access to drugs include compassionate use protocols and
enrollment in clinical trials.

committee is interested in formalizing the accumulation, integration, and

communication of that increased and improved knowledge.
In both the preapproval and the postmarketing setting, the risk-benefit
analysis that currently goes into regulatory decisions appears to be ad hoc,
informal, and qualitative. For preapproval, review divisions work relatively
autonomously under general guidance on how to review applications in the
absence of clear guidelines about how to make the final decision regarding
approval (FDA, 2005c). Some variability is necessary, due to the very nature
of the drugs themselves. Considerations regarding the balance of efficacy
and safety for a new drug to treat a fatal condition are different from those
for the tenth drug in a therapeutic category to treat minor symptoms. How-
ever, variability in how review divisions operate is of concern to industry
(Tilson et al., 2006) and to CDER. CDER leaders have expressed interest
in standardizing their means of analyzing risk and benefit and in doing so,
when possible, in an integrated way. A recent study by Boston Consult-
ing Group performed for Pharmaceutical Research and Manufacturers of
America (PhRMA) confirms that CDER lacks standard approaches to this
important responsibility (Tollman, 2006). Consistency in the approval pro-
cess will benefit the drug sponsors in preparing their NDA packages and in
planning postmarket study commitments.
In addition, increased efforts at risk-benefit analysis will help support
postapproval decision making by regulators, drug sponsors, physicians,
and patients. More robust risk-benefit analyses can provide quantitative
estimates that may be useful to clinicians and patients in deciding whether
to use a medicine. For example, a recent publication summarizing safety
outcomes from the WHI used a relatively simple table to present results from
that study (see Table 4-1). The WHI was three large clinical trials in one,
and the major interventions were hormone replacement therapy, low-fat
diets, and calcium plus vitamin D. The main outcomes for the comparison of
estrogen plus progestin with placebo are summarized in the table (Women’s
Group for the Women’s Health Initiative Investigators, 2002). When all
types of outcomes are treated as equal, hormone replacement therapy is
associated with an overall increase in adverse health events of about 20
per 10,000 women per year. Women will vary in their baseline risk of these
types of disease conditions; however, they will also vary in the preferences
for avoiding one type of disease condition or another as well as in their
views about the value of symptomatic relief from menopausal symptoms.
The information from the WHI trial provides patients and physicians with a
useful empirical basis for the discussion of risks and benefits relating to the
use of combined hormone therapy. Moreover, risk-benefit analyses can help
to identify what key questions remain to be answered and thus generate the
most important issues or hypotheses that require additional study.
Integrated comprehensive quantitative assessments and weighing of

TABLE 4-1 One-Year Increase or Decrease in the Number

of Major Health Outcomes Among 10,000 Women Taking
Estrogen Plus Progestin Compared with Women Taking Placebo
Event Type Number*
Coronary heart disease +7
Stroke +8
Pulmonary embolus +8
Invasive breast cancer +8
Colorectal cancer –6
Hip fracture –5
Total +20
*A plus sign means that, compared with placebo, there were more events in
the women taking hormone therapy, and a minus sign means that there are fewer
events in the women taking hormone therapy.
SOURCE: Adapted from Women’s Group for the Women’s Health Initiative
Investigators (2002).
risks and benefits are far from perfect. Some misleading analyses (with
resulting inappropriate regulatory or clinical decision making) are likely
because of imperfect information. Nevertheless, the potential advantages
of having a systematic approach to risk-benefit analysis for prescription
drugs include increasing consistency of approach to approval decisions
among the review divisions; a growing common understanding about the
criteria for approval and other regulatory actions; increased transparency
for the industry, health care providers, patients, and researchers; increased
credibility of FDA and CDER; and direct assessments of comparable drugs.
Ideally, the weighing of a product’s risks and benefits will be both transpar-
ent and reproducible.
The barriers to moving pharmaceutical risk-benefit assessment toward
a more systematic and scientific endeavor include those related to data and
to methods. Data are a primary rate-limiting factor in the evaluation of
risks and benefits. Information on a drug’s risks and benefits comes from
preclinical and clinical studies, but it is phase 3 clinical trials that provide
the bulk of the data used to make risk-benefit determinations at the time
of approval. Risk or safety assessment is limited by what is missing. Most
important for risk assessment is the lack of information that would enable
estimation of event rates, their comparison across treatment groups, and
evaluation of causality. Findings from preapproval clinical trials may suggest
safety signals, but the numbers of events tend to be small and may not lend
themselves to precise statistical analyses. The trials lack the ability, both
because of their size and because of the relative homogeneity of the typical
clinical trial population, to yield confident statements about the plausible

range of risks that would affect the populations who would actually take
the drug if it were approved. Therefore, when a safety signal is apparent but
uncertain, in some cases additional studies should be designed to reduce the
uncertainty about potential risk. Benefit data may also be limited by what is
missing, namely, information on health benefits if the approval was based on
surrogate endpoints rather than health outcomes. Also typically lacking is
information on risk-benefit relationships in important subgroups of patients
(such as those with severe disease or comorbidities), or large numbers of
patients exposed to the drug for long durations, or results of other treat-
ments (head-to-head trials), and on long-term health outcomes.
Regarding methods, a growing set of tools can be used to attempt to
quantify the value of research. Because the results of a research program
are intrinsically uncertain, the tools are based on a “value of information”
approach that identifies the value of research as the expected value of the
improvements in outcomes that would be generated by a research project
(Meltzer, 2001; Claxton et al., 2005b). The techniques to guide research
priorities are beginning to be used in other countries to assess when addi
tional research on a drug should be required as part of a regulatory deci-
sion. For example, in the United Kingdom the National Institute for Health
and Clinical Excellence has begun to explore the use of the approaches to
evaluate research priorities (Claxton et al., 2005a). Quantitative measures
of treatment benefits and the application of risk-benefit analysis should
consider such factors as the seriousness of a disease, its chronicity, and the
effect of a drug on quality of life or the disease process.
Metrics that have been used to measure benefits include absolute differ-
ences in event rates, mortality, number of lives saved, and quality-adjusted
life years (QALYs) (the relative differences are not nearly as helpful as the
absolute ones in this setting). Quantifying benefits in terms of those metrics
is difficult or impossible if efficacy is assessed only in terms of surrogate
endpoints. Risks can be summarized in terms of incidence, risk difference,
excess risk, severity, and duration. Rates and risks are quantitative, but only
the more common events that occur with enough frequency in premarket
clinical trials can be incorporated into the metrics with any precision. As
the comittee learned in its workshop (see Appendix D for the workshop
agenda), the science and the acceptance of approaches to simultaneously
and explicitly considering multiple benefits and risks for pharmaceuticals
and their preferences is evolving (Weiss Smith, 2006).
4.5: The committee recommends that CDER develop and con-

tinually improve a systematic approach to risk-benefit analysis
for use throughout the FDA in the preapproval and postapproval
settings. The systematic approach should have the following
characteristics:

• Use the most rigorous possible scientific methods to provide guid-

ance about what information should be collected and how that
information should be analyzed and used for decision making.
• Help assure that the studies required to conduct risk-benefit
analyses are properly designed to answer key public health ques-
tions and completed in a timely fashion.
• Make the product of these analyses available to patients, physi-
cians, policy makers, and researchers in terms that will aid their
decision making. Information on the specific consequences (such
as treatment benefits and adverse effects) of therapeutic options,
and the level of uncertainty about those consequences should be
provided for all drugs.
• Provide when possible population-level measures of effectiveness
and cost-effectiveness using standard measures that aggregate
across domains of health (such as QALYs) to help inform ap-
proval and coverage decisions.14
• Calculate when possible the expected value of research to guide
recommendations about when to perform additional studies.
• Provide guidance about what new data are needed and how those
data should be analyzed.
• Be updated as new information becomes available.
• Be described in publicly available documents that are appropri-
ate for all stakeholders.
The benefits of the effort will be harmonization of the work of differ-

ent review divisions, a growing understanding of the criteria for approval
and other regulatory actions, and increased transparency for the industry,
healthcare providers, patients, and researchers. The committee believes that
with the tools described above, the evidence base on the risks and benefits
associated with drugs will be more complete and will serve the health of
the public better. In addition to generation and evaluation of data, the drug
safety system must be viewed by the public and the prescribing community
as credible. The next section describes some concrete steps that will reas-
sure the public that the science on which FDA makes regulatory decisions
about risks is credible.
CREDIBILITY OF THE SCIENCE

As has already been discussed extensively, uncertainty about benefits
and risks is common throughout much of a drug’s lifecycle. Once safety
14FDA does not make coverage decisions or consider cost-effectiveness, but other partners
in the drug safety system do, and this information will be valuable.

signals begin to emerge, unless observational studies or controlled trials are

done to examine safety endpoints, difficult judgments about the meaning of
data that are less than perfect data must be made. As Chapter 3 describes,
CDER’s functioning is stressed when there is disagreement about the best
course of action in the face of uncertainty. It is important that CDER staff—
and industry sponsors, healthcare providers, and patients—believe that
the best decisions possible have been made. Confidence in the judgments
depends on the expertise of those informing the decisions, their wisdom and
leadership ability, and the transparency of the information itself.
Expertise in the Center for Drug Evaluation and Research

The committee has made several recommendations to expand the data
on drug risks and benefits to improve decisions. However, appropriate ex-
pertise must be brought to bear to plan research and use the resulting data.
That expertise comes from the CDER staff and their advisory committees
and other non-governmental experts. The committee believes that there is
a need to expand the available expertise to take on the new responsibilities
described in recommendations made in this report. CDER will need more
expert staff, deeper expertise in the staff it already has, and different kinds
of expertise.
4.6: The committee recommends that CDER build internal epi-

demiologic and informatics capacity in order to improve the post-
market assessment of drugs. In recognition of the human resource
limitations in the current employment market to meet this role, a
combination of advancing professional skills through continuing
education and support for academic training programs is needed.
Informatics experts should track progress on the national health-

information infrastructure, look for opportunities to gather information
about drug safety and efficacy after approval, coordinate partnerships with
external groups to study the use of electronic health records for AE surveil-
lance, participate in FDA’s already strong role in setting national standards
and track the development of tools for data analysis in industry and aca-
deme, and encourage the incorporation of the tools into FDA practice where
appropriate.
Expanded epidemiologic expertise will allow ODS/OSE to apply more
sophisticated methods in extracting information from the case reports
from the passive-surveillance system and information from administrative
databases. ODS/OSE staff could serve as principal investigators for some re-
search projects in the expanded epidemiology-contracts program; this could
help in recruitment and retention of staff. In addition, the increased sophisti-

cation regarding epidemiologic methods could lead to more productive and

respectful interactions with other CDER staff, advisory committee members,
and industry scientists. The recommendation in the preceding chapter that
would give ODS/OSE staff more responsibilities in both preapproval and
postapproval settings will require increased capacity in numbers of staff
and in the expertise that ODS/OSE staff contribute.
However, expanding epidemiologic capacity in CDER staff may be chal-
lenging. Few academic centers are capable of providing appropriate training
in pharmacoepidemiology. That has led to a national dearth of adequately
trained personnel in drug safety and risk management (Lo Re and Strom,
2006). A recent commentary from the International Society of Pharmaco-
epidemiologists echoes the concern for Europe as well (ISPE, 2006).
Options for improving training in drug safety and risk management
have recently been proposed to the committee (Lo Re and Strom, 2006).
The federal government has never offered career-development awards in
pharmacoepidemiology, except to those whose interests matched the inter-
ests of categorical institutes of NIH, which allowed them to apply to those
institutes for mentored career development awards, such as the K01, K08,
and K23 Awards. The only federal funding now available for training in
pharmacoepidemiology is in the CERTs program (see below). The National
Institute of General Medical Sciences is about to award its first pharmaco-
epidemiology training grant in its clinical pharmacology training program.
However, it will contain only two slots per year—this is far too few to meet
the needs of FDA alone, much less those of the field in general.
Increasing the epidemiologic capacity of CDER, focusing on ODS/OSE
but also in OND if desired, could take the form of hiring new staff with
training in epidemiology in addition to their professional medical, nursing,
or pharmacy training or could be accomplished through targeted programs
of training of existing ODS/OSE staff. That could range from short courses,
to the support of degree programs at either the master’s or the doctoral
level, to a formal training program, such as the Epidemic Intelligence Ser-
vice program at CDC.15 A first step in laying out the options for increasing
training opportunities could be a committee of ODS/OSE and OND staff
with input from epidemiologists from CDC, NIH, AHRQ, and other FDA
centers. Priority should be given to training programs with direct links to
advancing the scientific work that underpins CDER’s regulatory mission.
With expanded expertise and resources, CDER could be a more ef-
fective steward of postmarket safety and a more credible scientific partner
with industry and academe by actively participating in defining important
15The committee has not done an independent assessment of how those options are used but
understands that they are all viable options.

research questions and designing appropriate studies. More details about

increasing CDER resources is presented in Chapter 7.
Increasing the scientific sophistication of the CDER staff should not
take place in isolation. The goal is to support good science-based regulatory
decision-making, and a corollary goal is to support the research infrastruc-
ture of the agency. There is a small research program in CDER and in other
FDA centers, but history shows a slow decline in that capacity. The com-
mittee notes with satisfaction the recent decision of the FDA Science Board
to look into ways to expand the research capacity in FDA.
FDA depends on research conducted by the regulated industry and by
academic scientists who are financially dependent on the industry. The com-
mittee believes that the scientific reviewers in CDER would be well served
by having opportunities to engage in scientific research that complement
but do not conflict with their regulatory duties. There is little opportunity
in CDER for OND and ODS/OSE reviewers (and possibly other offices as
well) to engage in research (DHHS and OIG, 2003). For example, the ODS
annual report for 2004 states that ODS staff were coauthors of three papers
in the peer-reviewed literature (all of which were with coinvestigators in the
cooperative agreement program). The FDA Center for Biologics Evaluation
and Research, CDER’s sister center, has a long history of research publica-
tion in many areas, including postmarket surveillance, as do epidemiologists
at CDC, and the committee urges that CDER encourage such efforts.
The progenitor of FDA, the Bureau of Chemistry established in the
Department of Agriculture in 1906, created at its inception the Food Re-
search Laboratory to underscore its commitment to science-based regula-
tion, and for over 50 years special advisory committees to the department
secretary or the FDA commissioner have repeatedly affirmed the central
importance of intramural scientific research to the functioning of the agency
(see Box 4-1).
Since 1955, at least six committees have consistently asserted the cen-
trality of high-quality scientific research to the regulatory missions of FDA
and called for major changes in the organization and management of the
agency’s scientific endeavors.
In response to those committees’ recommendations, FDA has estab-
lished (and then disestablished) multiple new research organizations (cen-
ters, bureaus, and at least one institute) and repeatedly recreated the senior
management position of scientific director under various names. History
indicates that those repetitive efforts all failed, and although the reasons
for failure are not self-evident, the record points to the common problem
of discordance among well-intentioned scientific aspirations, ever-increasing
regulatory mandates and complexities, and annual budgets that were
chronically insufficient to accommodate the desired objectives.
The admonition of the 1991 advisory committee that the agency “avoid

BOX 4-1
History of Reports Regarding Research at FDA
In 1955, the report of the Citizen’s Advisory Committee on the Food
and Drug Administration to the secretary of health, education, and wel-
fare, stated: “Research is the heart of any scientific operation. Although
the FDA is primarily a regulatory agency, it must engage in research of
the sort that leads to more accurate scientific methods for determining
whether a food or drug is safe. Such research in scientific methodology,
and perhaps a limited amount of what might be termed ‘random research,’
can do much to upgrade the professional competence, elevate the morale
of scientific workers, and contribute to the general effectiveness of the
FDA.”
In May 1991, the final report of the Advisory Committee on the Food
and Drug Administration, convened by the secretary of health and human
services asserted: “In an era of rapid technological advancement, the
FDA must reaffirm its commitment to research as an integral component
of its activities. The FDA’s intramural and extramural research projects
must be linked to the Agency’s primary functions . . . High levels of scien-
tific expertise are required to review product applications and to respond
to public health crises . . . FDA scientists who are actively engaged in
research help build a vital foundation of Agency understanding and ex-
pertise. Without that foundation, the Agency’s ability to address emerging
regulatory problems is hampered. It is essential that the FDA avoid being
blind-sided by rapid advances in biomedical science and technology.”
For more information see: Science Board to the Food and Drug Admin-
istration. 1955. Appendix D, An Abbreviated History of at Least Four
Decades of Efforts to Upgrade the Quality of Science in the FDA.
being blind-sided by rapid advances” in biomedical and other sciences and

technologies resonates with the present committee, which reaffirms the
importance of a robust program of intramural scientific research to inform
FDA’s regulatory deliberations and actions. Such an intramural program
would provide an excellent interface with the agency’s relatively modest
investments in extramural research conducted by CERTs and other contrac-
tors. The committee applauds those extramural investments and does not
intend that they be threatened by the recommended strengthening of the
intramural research program. On the contrary, the committee believes that
there is an abundance of extraordinary research opportunities that could
substantially enhance the agency’s regulatory processes with respect to both
the efficacy and the safety of new therapeutics. Many of the opportunities

involve the creation and application of new algorithms and methods to

improve the processes of preclinical and clinical drug development and new
processes to enable effective safety and efficacy monitoring and evaluation
over the entire lifecycle of a therapeutic. If FDA is to take advantage of the
many research opportunities, research must be recognized as critical to its
core mission and be adequately funded. Opportunities for research bring
opportunities for real and perceived conflicts of interest, and the commit-
tee urges that these be watched carefully. The committee urges that the
research opportunities be linked explicitly to FDA’s regulatory mission. The
committee affirms that a strong program of intramural scientific research
provides an essential foundation for sound, science-based regulatory policy
and performance.
4.7: The committee recommends that the Commissioner of FDA

demonstrate commitment to building the Agency’s scientific re-
search capacity by:
a. Appointing a Chief Scientist in the office of the Commissioner

with responsibility for overseeing, coordinating, and ensuring
the quality and regulatory focus of the agency’s intramural
research programs.
b. Designating the FDA’s Science Board as the extramural advi-
sory committee to the Chief Scientist.
c. Including research capacity in the Agency’s mission statement.
d. Applying resources to support intramural research approved by
the Chief Scientist.
e. Ensuring that adequate funding to support the intramural
research program is requested in the Agency’s annual budget
request to Congress.
Advisory Committees
Chapter 2 describes some basic characteristics of FDA drug-product
advisory committees. Those experts and their input constitute an important
resource for FDA in tackling particularly difficult or challenging questions
related to its regulated products. Scientific advances, changing technology,
and the increasing complexity of new drug products have necessitated the
establishment of a strong advisory committee system. Through its advisory
committees, FDA can seek advice experts from outside the agency who serve
as “special government employees”. The system enables FDA to tap into
critical expertise at major research institutions.
Advisory committees are used as a source of independent advice about
questions raised by the agency regarding new drugs in the review process,

safety or efficacy issues that emerge after drug approval, methodological

approaches in study design, conduct or analysis, and policy issues. Com-
mittees may be asked to comment on whether there are sufficient data to
support product approval. They may be asked to comment on some aspect
of safety, effectiveness, or clinical development peculiar to a product. They
may also be asked to recommend whether additional studies are needed
for some products or whether changes should be made to a drug’s label in
response to new risk information. Typically, after presentations by the spon-
sor, agency representatives, and a public comment period, advisors will vote
on the questions posed to them. Advisory committee recommendations are
not binding, but the agency usually abides by them.16
FDA uses its advisory committees selectively because of time and cost
considerations. Typically, advisory committees are involved in decisions
involving new or complex technologies or issues that involve some element
of controversy. Advisory committees tackle issues that do not have simple
answers. Soliciting the advice of an advisory committee is usually at the
discretion of the division director of one of FDA’s five product centers.
Advisory committees promote several goals of the agency. They con-
tribute to the quality of agency decisions and ensure that important public
health decisions are based on informed and expert advice. They also increase
the transparency of those decisions in that the transcripts of all meetings and
the material presented at the meetings are made public, and the meetings
receive much mass-media attention. The use of such critical outside expertise
to inform agency decision-making lends credibility to the agency’s decisions.
In addition, because advisory committees always include a consumer or
patient representative to provide insight or feedback about the public’s or
patient’s perspective, those meetings are among the few opportunities for
the public to play an active role in FDA decisions. Participation in the public
comment period is another such opportunity.
The present system has served the agency well, but several factors have
made the use of advisory committees more challenging. Review deadlines
adopted as part of PDUFA have made it increasingly difficult for the agency
to convene advisory committees for questions related to product approval.
With review deadlines for priority-rated drugs set at 6 months (10 months
for standard-rated drugs), the agency is hard pressed to complete its review,
formulate its questions for the advisory committee, and then schedule the
meeting within a timeframe that permits these 6-month deadlines to be
met. Such committees typically must be scheduled 2 months in advance, so
regulators cannot fully anticipate the questions or problems that they will
encounter in the review process (DHHS and OIG, 2003; IOM Staff Notes,
16It is precisely the practice of following advisory committee recommendations that makes
the Plan B controversy so notable.

2005–2006). The problem is mainly one of logistics, timing, and complying

with the regulations for using special government employees, including the
process for considering conflict of interest.
Some in the agency have suggested that the review deadlines have forced
them to plan for advisory committee input too early in the process, before
the questions to be presented have been fully developed and the appropri-
ate expertise is fully recognized, and hence reduced the effectiveness of this
important agency resource. Data also show that from 1998 to 2001 there
was a 50 percent reduction in the agency’s use of advisory committees for
approved NMEs and priority drugs (DHHS and OIG, 2003). NMEs and
in particular priority-rated drugs are the most innovative and complex
new drug products and have been shown to be associated with increased
drug risks (Olson, 2004). Although reduction in product submissions has
contributed in part to the decline in use of advisory committees, FDA man-
agers indicate that they have little time to hold advisory committee meetings
within the current review deadlines (DHHS and OIG, 2003:11–12). The
reduction in the use of the committees has important implications for the
agency. Reduction in input from informed independent experts may reduce
the quality of the decisions and thereby lead to a reduction in public confi-
dence in the agency. Reduction in use of advisory committees also reduces
the public’s role in FDA decisions and reduces the transparency and perhaps
the credibility of the regulatory decisions in the public’s mind.
4.8: The committee recommends that FDA have its advisory com-
mittees review all NMEs either prior to approval or soon after ap-
proval to advise in the process of ensuring drug safety and efficacy
or managing drug risks.
The committee recognizes that it might be impossible for all NMEs to

be reviewed by an advisory committee before approval, because of the time
constraints described elsewhere. However, it believes that such review is
important and allows for review of the drug after approval if preapproval
review is not possible. If FDA is granted the authorities that the commit-
tee believes it should have (as described in Chapter 5), there will ample
opportunity for useful input even after approval. Careful review of phase 4
study designs by advisory committees and/or by the public-private partner-
ship should obviate concerns that giving CDER more control over phase 4
studies could be wasteful and inefficient. The goal is for better-designed
studies that will be conducted and answer needed questions.
The committee has concerns about the composition of product-specific
advisory committees. Traditionally a statistician serves on these committees,
but other than Drug Safety and Risk Management (DSaRM) Committee,
there is no guidance related to epidemiology or other public health expertise.

Because consideration of risk and benefit often depends on understanding

the population perspective and review of observational studies and because
drug safety problems are not reviewed only by DSaRM, the committee
would like to ensure that the recommendations of advisory committees are
based on a broad spectrum of disciplinary expertise.
4.9: The committee recommends that all FDA drug product ad-
visory committees, and any other peer review effort such as men-
tioned above for CDER-reviewed product safety, include a pharma-
coepidemiologist or an individual with comparable public health
expertise in studying the safety of medical products.
In addition to concerns about advisory committee expertise and appro-

priate review, the committee shares concerns about the appearance of inde-
pendence of advisory committees as it is affected by financial relationships
of members with pharmaceutical or other private interests. In making the
determination of whether a financial interest poses a conflict, FDA applies
the terms of two statutes, 18 U.S.C. § 208, and 21 U.S.C. § 505(n). Under
both, FDA may grant a waiver of any conflict of interest provided that some
criteria are met. In addition, both statutes provide for public disclosure of
financial interest information when a waiver has been granted (see 18 U.S.C.
§ 208(d)(1) and 21 U.S.C. § 355(n)(4)).
The guidance “FDA Guidance on Conflict of Interest for Advisory Com-
mittee Members, Consultants and Experts” describes the type and amount
of information that is considered in deciding whether a financial interest
presents a potential conflict of interest that needs to be merely disclosed
or needs to be reviewed by the ethics staff for consideration of a waiver
regarding a topic to be discussed by the advisory committee whose meet-
ing the special government employee is attending (FDA, 2000). Table 4-2
describes key information considered as a level of financial interest that
is transmitted to the ethics staff in a memo but does not require a waiver
although it is disclosed to the public. For interests that exceed such levels,
FDA uses a “sliding scale” to decide whether levels of conflict of interest
are acceptable. Levels are different for participation in a “general matter”17
17A particular matter of general applicability is a matter that is focused on the interests of a
discrete and identifiable class of persons but does not involve specific parties. For example, a
guidance document that affects an entire class of products and all similarly situated manufac-
turers is a matter of general applicability. In addition, the use of a potential product solely as
a model or example for general discussion whose results will apply to a class of products may
be a matter of general applicability.

TABLE 4-2 Conflicts of Interest That Lead to a “Cover Memo” Only

(Disclosure Required, but Waiver)
Type of
Conflict of
Interest Party Matters General Matters Any Matter
Stocks and Stock value is less than Stock value is less than
Investments or equal to $5,000 or equal to $25,000 per
in aggregate (5 CFR entity/$50,000 in aggregate
2640.202(a) de minimis (5 CFR 2640.202(b) de
exemption) minimis exemption)
Primary SGE is a federal employee Matters will not have a

Employment and his agency, not his special or distinct effect
organizational component, on the SGE or employer,
is conducting research on the committee’s decision
the product under review— may affect SGE/employer
funding from the sponsor is only as a part of a class
less than $500,000/per year of product manufacturers
(5 CFR 2640.203 (g)
exemption for non-Federal
employment interests
of SGEs on advisory
committees)
SGE is a federal
employee, and his agency
is conducting research
for one or more firms
with an interest in the
general matter before the
committee
continued

TABLE 4-2 Continued

Type of
Conflict of
Consultant/ SGE receives less than SGE receives less than
Advisor $10,000 per source per $10,000 per source per
year and consulting on year and consulting on
unrelated issue in the past related or unrelated issue
or completed within the completed within the past
past 12 months (all monies 12 months (all monies paid)
paid)
SGE receives between
SGE receives between $10,000 and $50,000
$10,000 and $50,000 per source per year and
per source per year and consulting on related or
consulting on unrelated unrelated issue completed
issue in the past or within the past 12 months
completed within the past (all monies paid)
12 months (all monies paid)
SGE receives more than
$50,000 per source per
year and consulting on
related or unrelated issue
completed within the past
12 months (all monies paid)

TABLE 4-2 Continued

Type of
Conflict of
Contracts/ Remuneration is less than Remuneration is less than
Grants/ $100,000 per source per $100,000 per source per
CRADAs year to institution/$10,000 year to institution/$10,000
per source per year as per source per year as
salary support to the SGE salary support to the SGE
and work on unrelated and work on unrelated
product is currently active matter is current or
or completed within the completed within the past
past 12 months 12 months
Remuneration is less than

$100,000 per source per
year to institution/$10,000
per source per year as
salary support to the SGE
and work on related matter
has been completed over a
year ago
Remuneration is between
$100,000–$300,000
per source/year to
institution/$10,000–
$15,000 per source/year as
salary support to the SGE
and work on unrelated
matter is current or
completed within past 12
months
Patents/ SGE receives less than

Royalties/ $15,000 in royalties per
Trademarks affected source annually
and SGE has a patent on an
unrelated product, licensed
by a competing firm, and
receives royalties
Expert Remuneration is less than

Witness $5,000 per affected source
per year and SGE makes
no statement for or against
any product of a sponsor or
competitor
continued

TABLE 4-2 Continued

Type of
Conflict of
Teaching/ SGE receives
Speaking/ less than $5,000
Writing per source per
year and topic is
unrelated to the
particular matter
and SGE receives
no compensation
SGE receives
less than $5,000
per source per
year and topic
is unrelated
and SGE is
compensated
SGE receives
less than $5,000
per source per
year and topic
is related but
SGE receives no
compensation
(including travel)
SGE receives
less than $5,000
per source per
year and topic is
related but not
specific to the
matter under
discussion by
the committee
and SGE is
compensated

TABLE 4-2 Continued

Type of
Conflict of
Department Remuneration is less than Remuneration is less than
Heads— $300,000 per source per $300,000 per source per
Contracts/ year to SGE’s department year to SGE’s department
Grants/ and work on unrelated and work on unrelated
CRADAs matter is current or has matter is current or has
been completed within the been completed within the
past 12 months past 12 months
Remuneration is less than Remuneration is less than

$300,000 per source per $300,000 per source per
year to SGE’s department year to SGE’s department
and work on related and work on related
matter has been completed matter has been completed
within the past 12 months within the past 12 months,
and SGE had only an and SGE had only an
administrative role administrative role
Remuneration is between Remuneration is between

$300,000–$600,000 per $300,000–$600,000 per
source per year to SGE’s source per year to SGE’s
department and work on an department and work on
unrelated matter is current unrelated matter is current
or has been completed or has been completed
within the past 12 months within the past 12 months
Remuneration is between
$300,000–$600,000 per
source per year to SGE’s
department and work on
related matter has been
completed within the past
12 months and SGE had
only an administrative role
Exceptions The interests reported are

for unrelated to the product at
Institutional issue or to the competing
Directors products (up to $750,000
per source per year)

and in a “party matter.”18 Higher levels of conflicting financial interests

require review by the DHHS ethics office and are balanced against the need
for a member’s expertise and unique contributions. Waivers can be granted
for the participation of members who have more than minimal financial
conflicts. That information is disclosed on the FDA Web site and is read at
the start of each advisory committee meeting. No policies limit the number
of advisory committee members receiving waivers who are allowed to vote
on any specific matter.
A recent analysis of over 200 CDER advisory committee meetings held
between 2001 and 2004 shows a weak association between the presence of
advisory committee members with conflicts of interest and the outcome of
votes to approve or not approve a drug for marketing (Lurie et al., 2006),
which supports a perception in some that advisory committee functioning
is less than independent. However, Lurie et al. acknowledge that “excluding
advisory committee members and voting consultants with conflicts would
not have altered the overall vote outcome at any meeting studied.” FDA
responded to the article with additional analyses of the data reviewed by
Lurie19 concluding “. . . advisory committee members and consultants with
financial ties to pharmaceutical companies tend to vote against the finan-
cial interest of those companies” (FDA, 2006). The committee notes that
concerns about voting patterns by waivered advisory committee members
presume that a vote by someone with a waivered conflict of interest is a
“wrong” or “incorrect” vote, but concludes that there is no evidence to
suggest that this is necessarily so.
Although some have proposed that there be a zero-tolerance policy
regarding conflict of interest on FDA advisory committees (H.R.2744 Sec.
795), others express concern that such a policy could lead to severely un-
derinformed advisory committees or leave a very small pool of potential
advisory committee members. The committee recognizes that many leaders
in academic medicine with experience designing and conducting clinical tri-
als receive research support from the pharmaceutical industry and that they
conduct their research in an unbiased manner. The committee also recog-
nizes that researchers who consult for industry gain important insights that
are needed in the review process. However, not all researchers with some
of the relevant expertise necessary for these advisory committees have cur-
rent or recent industry funding (of consultancies or the conduct of clinical
18A particular matter involving specific parties focuses on a specific product application or
other matter affecting a specific manufacturer and its competing products or manufacturers
(such as NDA, PMA, PLA or BLA, or efficacy supplement for a new indication). That is, it
focuses uniquely and distinctly on a given product/manufacturer.
19Including votes by advisory committee members with conflicts of interest related to rela-
tionships with companies that would be considered competitors to the drug whose approval
was being voted upon.

trials). NIH, for example, funds clinical trials, and investigators associated
with those would bring necessary practical expertise to a drug products
advisory committee. The committee also recognizes that financial conflicts
are not the only conflicts that could influence votes. It is hard to screen out
or to waive positions of intellectual bias (Stossel and Shaywitz, 2006). The
committee supports narrowing the policies in place today but acknowledges
the difficulties of convening sufficient experts for the numerous advisory
committees that review drug products. The committee supports a position
of nonwaivable limits, but not a zero-tolerance policy, for financial conflicts
of interest on FDA drug-product advisory committees.
4.10: The committee recommends FDA establish a requirement

that a substantial majority of the members of each advisory com-
mittee be free of significant financial involvement with companies
whose interests may be affected by the committee’s deliberations.
The committee supports 60 percent as a reasonable definition of
substantial majority and believes that a reasonable definition of
free of significant financial involvement are those involvements
that currently require only disclosure and do not require a waiver
(see Table 4.2 for a summary). The committee urges that FDA issue
waivers for the participation of the other 40 percent of advisory
committee members very sparingly. The committee also urges that
FDA routinely analyze the effect of their conflict-of-interest policies
in protecting the objectivity and quality of committee activities. The
committee further urges that each posting of an advisory commit-
tee transcript be accompanied by a list of waivers granted and that
FDA publish a yearly summary of the number of waivers granted
per advisory committee.
Most members of advisory committees work in academic institutions,

particularly medical schools and teaching hospitals, and policies of those
institutions can help to protect the integrity of those who serve. That is
particularly important because the pool of experts in pharmaceutical policy
who are free of financial conflicts appears to be shrinking. Pharmaceutical
support of research and other academic and medical activities is wide-
spread—a fact that the committee views with some concern. In that vein,
it would be helpful if all universities and nonprofit academic healthcare
institutions promulgate and enforce rigorous conflict-of-interest policies
governing academe-industry relationships on the part of their faculty and
their institutional leaders. At a minimum, such policies should require
disclosure in all publications, speaking engagements, and consultations
with government of any relationships with the pharmaceutical and device
industries. Policies should also conform with recommendations concerning

conflicts of interest developed by the Association of American Medical Col-

leges. All universities and nonprofit academic health care institutions should
have standing conflict-of-interest review committees that are independent
of their technology-transfer functions and are staffed by professionals who
are experienced in managing conflicts of interest.
Transparency
All stakeholders in the drug safety system have a legitimate interest in
understanding the data on which drug availability in the marketplace de-
pends. Not all people are interested in firsthand knowledge of the science
and depend on the decisions of others (such as their physicians and regula-
tor) to assure them that drugs they take are safe and effective. Others wish
to have more knowledge of the data. Many data are made public in some
form, at some time, and at some place on the FDA or another government or
industry Web site, but the process is not systematic, comprehensive, or well
organized. The committee believes strongly in the importance of increasing
the availability to the public and to researchers of information about drug
risks and benefits, whether specific study results or analyses of concerns by
agency staff, and it provides several recommendations related to clinical
trial registration and results reporting, Web-site posting of all NDA-review
packages, and timely public release of all CDER summaries of emerging data
relevant to the safety and effectiveness of a drug after approval.
As described in Chapters 2 and 3, information related to the efficacy
of drugs approved for use in the United States is examined in extensive
detail in the reviews prepared by CDER staff. Most of those review pack-
ages are posted on FDA’s Web site and summarize a significant amount of
data supporting the approval of the drug, yet these postings do not include
the entirety of what is known about a drug. A sponsor’s NDA is not made
public (even in redacted form to protect proprietary interests), and FDA
reviews of an NDA are not made public if approval is not granted. Those
reviews of unapproved NDAs could provide valuable information about a
drug if the application is a supplemental NDA or if it is for a new member
of a class of products already on the market. Although pharmaceutical
companies are required to submit to FDA information about all studies
conducted under an IND, results of studies that are not submitted as part of
a sponsor’s application package for approval or are finished after approval
are not necessarily disclosed to the public. There is no way to know the
results of clinical trials involving a drug if those results are not submitted to
the FDA as part of an NDA or other review package or are not published
in the scientific literature.
Several important efforts in recent years are aimed at increasing the
availability of at least a minimum of information about current or complet-

ed clinical trials. A recent Institute of Medicine (IOM) workshop provided

a summary of the major initiatives by DHHS, the pharmaceutical industry,
international medical journal editors, and the World Health Organization
(WHO) (IOM, 2006). The requirement in the Food and Drug Administra-
tion Modernization Act of 1997 (FDAMA) that the federal government
develop a way to register clinical trials of drugs intended to treat serious
or life-threatening diseases led to the creation of ClinicalTrials.gov in the
National Library of Medicine. Section 113 of FDAMA specifically requires
companies to register a trial conducted under an investigational NDA if it
is for a drug to treat a serious or life-threatening disease or condition and
is a trial to test effectiveness (42 U.S.C. 282(j)(3)(A)). The trial must be
registered no later than 21 days after enrollment is opened. Companies can
register nonrequired trials in the databank as well. As of July 1, 2006, more
than 30,000 trials have been registered on the site. PhRMA encourages its
members to do so voluntarily for all hypothesis-testing20 studies required
for the condition being studied.
This registry, which in recent years has won broad acceptance by in-
dustry, requires the completion of 20 data fields, developed by the WHO
as a “minimum required dataset” for full registration, and provides regu-
larly updated information about federally and privately supported clinical
research in human volunteers. The minimum required dataset provides
information about a trial’s purpose and the therapeutic agent being tested,
its primary and secondary hypotheses and prespecified endpoint(s), who
may participate, locations, and contact information for more details. It does
not, however, include the results of the trials, nor does the registry program
have the resources to do so.
In 2002, pharmaceutical companies that are members of PhRMA com-
mitted to voluntary disclosure of the results of hypothesis-testing clinical tri-
als for marketed and investigational drugs; and in 2004, PhRMA launched
the Web site ClinicalStudyResults.org for this purpose. A review of the site
shows great variability in the ease of accessibility and completeness of the
information. In addition, in the past few years many drug sponsors have
created their own “registries” on company Web sites, which list their clinical
trials, and may list summaries of trial results. These voluntary commitments
may signify good intentions for increasing transparency, but the history
leading to their introduction may, on the other hand, suggest that they may
rather represent efforts to avoid mandatory disclosure of results.
20“Also known as “confirmatory” clinical studies, hypothesis-testing studies are always well-
controlled and are intended to provide meaningful results by examining pre-stated questions
(i.e., hypotheses) using predefined statistically valid plans for data analysis, thereby allowing
firm conclusions to be drawn to support product claims. Hypothesis-testing studies may occur
at any stage of drug development and include all phase III studies, some earlier-phase studies,
and many studies of marketed products” (Clinicalstudyresults.org, 2006).

4.11: To ensure that trial registration is mandatory, systematic,

standardized, and complete, and that the registration site is able
to accommodate the reporting of trial results, the committee rec-
ommends that Congress require industry sponsors to register in
a timely manner at clinicaltrials.gov, at a minimum, all phase 2
through 4 clinical trials, wherever they may have been conducted,
if data from the trials are intended to be submitted to the FDA as
part of an NDA, sNDA, or to fulfill a postmarket commitment.
The committee further recommends that this requirement include
the posting of a structured field summary of the efficacy and safety
results of the studies. The committee does not offer specific details
regarding this summary, preferring that NIH and FDA, in consul-
tation with the pharmaceutical industry, should work together to
agree on a reasonable plan.21 However, the committee suggests that
mandatory fields could include, but are not limited to, (1) primary
hypothesis, (2) experimental design, (3) primary predefined out-
come measure(s), (4) planned and actual sample size per treatment
arm, (5) number and type of serious AEs, (6) overview of results,
and (7) risk-benefit summary. The company should have the respon-
sibility of submitting the structured field summary to the FDA, who
should review it for completeness and accuracy. The information
should then be posted either on an easily accessible Web site at FDA
with linkage to the trial’s registration on clinicaltrials.gov, or posted
directly on the latter.
For those clinical trials covered by this recommendation, every com-

pleted trial would have to comply with this mechanism of results reporting,
regardless of trial outcomes. For every covered trial that is stopped before
prespecified completion, the sponsor would have to submit a summary
describing the reasons for termination (Drug Safety Management Board
action, economic considerations, etc.) to FDA/NIH for review and posting.
The committee did not attempt to resolve what to do about postmarket
studies conducted by investigators independent of industry. If these stud-
ies are federally funded, the funding agency could require as a condition
of award that the lead investigators prepare and submit the structured
summary to clinicaltrials.gov after publication of the study. Enforcement
mechanisms for studies not conducted under federal grant/contract support
are less clear. The committee believes that to ensure that results to be posted
21Because the committee is not suggesting that raw data be posted, this recommendation
should provoke no concerns regarding patient privacy. The committee recognizes that this
recommendation will require significant additional resources to NIH, which runs clinicaltrials.
gov, and to FDA, for their role in developing the results format and vetting the submissions.

that are not vetted by the FDA are described completely, accurately, and in
an unbiased manner, clinicaltrials.gov would have to establish some form
of editorial review process. The National Library of Medicine, which runs
clinicaltrials.gov, will need to be provided the necessary authorization and
resources to accommodate results posting.
The format of clinical trial registration and results reporting should be
done in a way that harmonizes with emerging international standards (such
as those specified by WHO, for example, the minimum required dataset
for registration, and the requirements for results reporting, in the ICH E3
Summary of Clinical Trial Results). The committee notes with interest the
recent WHO call for registration of all interventional trials. The committee
strongly urges the Congress to consider the status and benefits of harmo-
nization with international standards when drafting legislative language to
implement this recommendation.
The committee also encourages further steps to make drug safety and
effectiveness information available to the public. The committee believes
that CDER is the appropriate body to assume the responsibility for sharing
important safety and efficacy information promptly and dependably with
patients, providers, and researchers. One important source of this informa-
tion at the time of approval is the NDA review package.
In response to the Electronic Freedom of Information Act Amendments
of 1996, which were designed to broaden public access to government
documents in electronic form, CDER posts NDA review packages22 on its
Web site (at the “drugs@fda” portion of the site http://www.accessdata.fda.
gov/scripts/cder/drugsatfda/). As of April 2006, review packages for NMEs
approved from 1998 to the middle of February 2006 and non-NMEs ap-
proved in 1998–2001 are posted. There is a backlog for posting review
packages for non-NMEs approved after 2001.23 All other NDA approval
documents (that is, for drugs approved before 1998 and for all supplements)
are posted on completion of a Freedom of Information Act (FOIA) request
for that information (D. Henderson, personal communication).
4.12: The committee recommends that FDA post all NDA review
packages on the agency’s Web site. Regardless of whether they
were disclosed in response to a FOIA request, FDA should post all
supplemental-NDA review packages and continue to work to post
reviews for drugs approved before 1998 in a timely manner and as
22Review packages are described in Chapters 2 and 3 and refer to the set of documents pre-
pared by CDER staff. These packages provide the summary judgment that leads to decisions
regarding approval.
23Of 531 non-NME NDA approvals since 2001, 397 had been posted on the Web as of
March 31, 2006, as had all the non-NME NDAs approved in 1998–2001.

resources allow. High priority should be given to posting all review

materials related to any product for which there are emerging safety
concerns, particularly if they have been discussed at an advisory
committee meeting.
OND and ODS/OSE staff prepare reviews or summaries of RiskMAPs

and other postmarket safety information and, if discussed at an advisory
committee meeting, these reviews are made public in accordance with the
Federal Advisory Committee Act; however, reports of general ODS/OSE
consultations are not, as a rule, made public. In 2005, ODS/OSE completed
439 reviews of postmarket safety issues (generated in ODS/OSE or as a
result of consultations for OND). Materials from advisory committees are
found on a portion of the CDER Web site distinct from that where the NDA
reviews are posted. There is no one place where every public document
regarding a specific drug is posted.
The committee recognizes that public disclosure of every internal docu-
ment discussing a potential safety problem has drawbacks. Any one docu-
ment likely describes only one aspect of a complicated topic. Full disclosure
of those documents in real time could be confusing to the public and does
not necessarily contribute to reducing the uncertainty about the risks and
benefits associated with a drug. However, there is a marked imbalance
between the disclosure of data accumulated before approval (the CDER
discipline reviews) and disclosure of data summarized and presented after
approval. The synthesis by CDER of postmarketing information that is
made public about risks and benefits is minimal. The committee believes
that CDER has a role to play in putting forth the views of the regulatory
agency about emerging information and should not leave that task in the
hands of the pharmaceutical industry or the academic community.24 Periodic
and regular review by CDER of risk and benefit information is consistent
with a lifecycle approach to drug regulation.
4:13: The committee recommends that the CDER review teams

regularly and systematically analyze all postmarket study results
and make public their assessment of the significance of the results
with regard to the integration of risk and benefit information.
Drug regulation must follow scientific advances; as science progresses,

so must regulation. The role of the regulator is not to impede the develop-
24Product safety specialists from the Center for Biologics Evaluation and Research routinely
develop reviews of the postmarket safety experience with a new vaccine within 2–3 years of
the time the vaccine is licensed. These reviews are published in journals and are available on
the FDA Web site’s VAERS (Vaccine Adverse Event System) page.

ment of innovative medicines, but to ensure that needed drugs are avail-
able to patients and that risk-benefit information is accurate and widely
available. The regulator must be the gatekeeper of the scientific foundation
on which regulatory decisions are made. CDER must have the best data
to review and an expert scientific staff to review them. Patients and their
physicians must be assured that the scientific foundation on which CDER
regulates drugs is credible.
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Regulatory Authorities for Drug Safety
Major components of the Food and Drug Administration (FDA) statu-

tory authority have evolved in response to drug-related public health crises
and in response to a changing environment. The social and health care
environment has changed and continues to evolve—health care providers
and patients expect timely access to effective drugs, the user-fee program
established in 1992 has increased the pace of drug review and approval,
the practice of medicine and the use of drugs have changed, and the infor-
mation available to the public from advertising and the Internet and from
commercial and government or nonprofit sources has transformed consumer
knowledge and the patient’s role in health care (see Chapter 1 for more
information). In view of those changes, the agency’s regulatory authority
must be reconsidered and strengthened to ensure that it is equal to the task.
However, the committee cautions against assuming that altering the statute
alone will solve all difficulties related to FDA’s regulatory authorities. FDA
needs considerable new resources to perform optimally in a fast changing,
challenging environment, including resources to support its regulatory ac-
tivities, such as regulatory oversight of direct-to-consumer (DTC) advertis-
ing and staff with training and expertise in drug regulation (see Chapter 7
for more discussion of resources).
This chapter briefly summarizes the history of drug regulation, de-
scribes the use of the agency’s authority during the preapproval and postap-
proval processes, identifies needed changes, and makes recommendations to
strengthen or clarify FDA’s authority.
151

HISTORY OF FDA DRUG REGULATION

The foundation of FDA’s regulatory authorities was laid in the 1906
Pure Food and Drug Act, which focused on misbranding and adulteration.
In keeping with other consumer product laws, it focused on postmarketing
remedies only. That is, if a drug already on the market was proven to be a
hazard, it could be seized and further sales halted.
In the wake of deaths due to elixir of sulfanilamide in 1937, the 1906
law was replaced with a stronger form of regulation in the Federal Food,
Drug, and Cosmetic (FD&C) Act of 1938. The new law changed the em-
phasis to the period of time before a drug enters the market, and required
manufacturers to notify FDA before beginning testing on human subjects
and to submit proof of the drug’s safety (though not of its efficacy) (Hutt,
1992). The requirement was a major advance in drug regulation, but it was
nonetheless still somewhat weak, as marketing could begin 60 days after
submission of the information to the FDA unless the FDA affirmatively
found the drug to be unsafe.
The statutory scheme for drug regulation went through yet another revi-
sion in 1962, after thousands of European children with limb defects were
born to mothers who had been administered thalidomide (Kaplan, 1995;
FDA, 2006). The Drug Amendments of 1962 shifted the burden of proof
from FDA (which previously had to prove harm to keep a drug from being
marketed) to manufacturers, who now were required to demonstrate both
safety and efficacy prior to receipt of marketing approval (Hutt, 1991). The
early 1960s also marked the crystallization of clinical trials into the sequence
of phase 1, 2, 3 trials still in use today and described in greater detail in
Chapter 2 (DHEW, 1963).
The FDA’s ability to form judgments about the safety and efficacy of
drugs depends upon the submission of data, usually from drug company
sponsors, rather than on the use of data developed independently or on its
own initiative. As a result, the statutory scheme governing drug approval in
the United States has also included a series of measures to provide an incen-
tive for third parties to develop safety and efficacy data for use by FDA. These
incentives include patent extensions (the Drug Price Competition and Patent
Term Extension Act of 1984), and periods of market exclusivity in exchange
for developing information about new drugs, new indications for old drugs,
and new information about the action of old drugs in special populations,
such as children (The Orphan Drug Act of 1982; The FDA Modernization
Act of 1997 [FDAMA]; the Best Pharmaceuticals for Children Act of 2002).
Thus, the statutory scheme is characterized by carrots rather than sticks,
in that the development of new information on drug safety and efficacy is
achieved more by creating incentives than by issuing mandates.
The 1938 FD&C Act, as amended several times, defines FDA’s regula-

REGULATORY AUTHORITIES FOR DRUG SAFETY 153
tory jurisdiction and its enforcement powers. The statute empowers FDA
to bring enforcement actions through administrative procedures (warning
letters, adverse publicity, recalls, and withdrawals of product approvals)
and judicial procedures (seizure, injunction, and prosecution) (Bass, 1997;
Levine, 2002). FDA’s enforcement authority is derived by delegation from
the secretary of the Department of Health and Human Services (DHHS) to
the commissioner of food and drugs (Bass, 1997). Regulations contained in
the Code of Federal Regulations empower FDA to enforce the FD&C Act
and other statutes, as appropriate. FDA’s ability to regulate is also influenced
by Congress and its “oversight jurisdiction” exercised by holding congres-
sional hearings (Hutt, 1991). The judiciary branch also may influence FDA
regulation, when FDA’s interpretations of the statute and its development
of regulations are successfully challenged in court.
AN AGING AND INADEQUATE STATUTORY FRAMEWORK

The statutory authority for drug regulation was constructed decades
ago, and it remains largely unchanged. The existing regulatory framework
is structured around the premarketing testing process; few tools are avail-
able for addressing postmarketing safety issues, short of the blunt instru-
ments to respond to clear-cut adulteration and misbranding. As described
in Chapter 1, the sciences of drug discovery and development, the practice
of medicine and the extent of drug use, and the information environment
in which health care providers practice and patients learn about drugs and
interact with the health care delivery system have all changed. It is time to
reassess and strengthen FDA’s postmarketing authorities and tools in view
of these changes. The carefully controlled clinical trials currently conducted
premarket under the existing statutory framework consists of study popula-
tions that are commonly different in composition and health status from
populations that will use the marketed drug. Study populations are chosen
for a legitimate reason: to make data from the trials clearer and thus to
make safety and efficacy testing more efficient. After approval, drugs are
used by larger and more heterogeneous populations, and by people who
have comorbidities or are taking multiple prescription and over-the-counter
drugs and dietary supplements. Furthermore, the promotion of drugs has
moved beyond health care providers, and substantial industry investment
goes into directly targeting consumers. It also has become more important
to recognize that the assessment of a drug’s risk-benefit profile does not
remain static after approval. Every effort must be made to monitor the
performance of drugs on the market, to identify safety problems early, and
to address them effectively. FDA’s ability to regulate drugs effectively in a
rapidly changing context requires reconsideration of the laws and a clarifica-
tion and strengthening of the agency’s regulatory authority.

Below, the committee describes main aspects and weaknesses of FDA’s

authority before and after approval.
FDA Authority Preapproval

A primary regulatory activity of the FDA Center for Drug Evaluation
and Research (CDER) is shepherding products through phase 1, 2, and 3
trials. If at any point during clinical trials, the agency “does not believe, or
cannot confirm, that the study can be conducted without unreasonable risk
to the subjects/patients”, the agency has the statutory authority to impose a
clinical hold on the trial (CDER et al., 1998). This suspends further progress
in the study until the underlying reasons for the hold (e.g., adverse events
or other safety questions) are addressed. Center review teams can also ask
sponsors to develop and submit for review, when appropriate, plans for
postmarketing safety surveillance and study to monitor previously undocu-
mented, unexpected risks, and a risk management program when there are
known risks. Other risk management measures and data from epidemiologic
studies may be needed if safety signals are identified and confirmed when
a drug has been on the market, including label changes, communication to
health care providers, restriction of marketing, and public health advisories.
In recent years, CDER has developed guidance for industry on preparing
and evaluating risk minimization action plans (RiskMAPs), which may in-
clude an array of educational and administrative activities to address risks
that are known at the time of approval.
There appear to be several conditions FDA can impose at the time of
approval, for example, requiring distribution limited to a specific medical
specialty, distribution with required periodic screening to avoid contraindi-
cated use, and distribution with mandatory enrollment in a registry. Certainly
such conditions have been imposed in the past, for example with teratogenic
drugs such as thalidomide and isotretinoin. However, varying interpretations
by occupants of the general counsel’s office of the FDA’s authority has led
to significant variation in the willingness of the FDA to consider using con-
ditions on sale as a condition of approval. And in general, such conditions
are even more difficult to put in place after the drug has been approved for
marketing, as efforts to impose such conditions nearly always depend upon
voluntary compliance by the manufacturer rather than on the threat of with-
drawal of the drug from the market as an imminent health hazard.
The Prescription Drug User Fee Act of 1992 (PDUFA) complicated
FDA’s ability to use its authority before approval. FDA’s existing statute
required that drug review be completed in 180 days; in practice, that goal
proved largely impossible to achieve (Kaplan, 1995). The desire of patients
and the general public for more rapid access to important drugs was among
the primary drivers of congressional action to speed up the drug approval

process. The enactment of PDUFA secured user-fee funds dedicated to

enabling FDA drug review divisions to retain the staff and other resources
needed to shorten the length of the approval process. PDUFA has clearly
expedited agency decision making and has probably led to efficiencies in
distinguishing important from less important issues in the final stages of
the review process. However, there is concern that the rapid pace of the
process needed to meet PDUFA goals (see Chapters 2 and 3) creates an
environment that makes it hard or close to impossible for CDER reviewers
to pursue safety concerns as carefully as they would in a less frenetic set-
ting (GAO, 2002b; DHHS and OIG, 2003; Levine, 2006; Nickas, 2006;
IOM Staff Notes, 2005–2006). Some also have serious concerns that the
regulator has been “captured” by industry it regulates, that the agency is
less willing to use the regulatory authority at its disposal (see Chapter 3).
Patient expectations and misperceptions about drugs, the ever broader
array of drugs, the complexity of actual drug use in the real world, and the
intense pace of preapproval activities all suggest that FDA needs stronger
authority postapproval to conduct adequate surveillance and oversee and
enforce safety studies.
FDA Authority After Approval

The primary expression of FDA’s authority is the threat to withhold or
withdraw approval; but because a drug may offer unique benefits to a popu-
lation in need, the threat of postapproval withdrawal can ring hollow.
Authority to Compel Completion of Postmarketing Commitments
Many postmarketing study commitments—a key activity requested by

the agency to help to narrow the remaining uncertainty about an approved
drug’s safety—are not met and many are never undertaken. As described
in Chapter 4, postmarketing studies are often planned and designed as an
afterthought late in the review process, just before approval, and sometimes
the study designs may not be the most useful, necessary, or even practicable
(IOM, 2005). That appears to be at least partly a result of the frenetic pace
of the review process, but it may also reflect the agency’s awareness of its
limited authority after approval.
FDA’s statutory authority to require postmarketing studies has been a
subject of debate for decades. Although the agency has interpreted FD&C
Act section 505(k), which grants it power to require “records and reports”
from sponsors as giving it the authority to mandate postmarketing studies,
this interpretation has been contested by the industry (Steenburg, 2006).
Several commissioners have admitted that the agency’s interpretation of the
statute made it vulnerable to court challenges. In 1977, the Review Panel

on New Drug Regulation also found that the statute did not give FDA that
authority. Many of the Panel’s recommendations were incorporated into the
1979 Drug Regulation Reform Act (S. 1075, Kennedy) which passed Senate
but failed to garner support in the House (DHEW, 1977; Steenburg, 2006).
The panel’s final report asserted that “rather than delay approval of a drug
pending additional studies, FDA should have the authority to require a spon-
sor to conduct additional research as a condition of approval when a drug
has been shown to be safe and effective for its intended use, but questions
remain, for example, with regard to its long term effects” (DHEW, 1977).
The 1979 bill included a provision to allow FDA to require postapproval
studies (Dorsen and Miller, 1979). The 1996 Inspector General found that
the FDA “tradition” of asking for voluntary postmarketing studies was not
supported by statute in most cases (DHHS and OIG, 1996).
FDAMA (which included the reauthorization of PDUFA) added a provi-
sion to the FD&C Act requiring sponsor submission of annual updates on
progress in meeting postmarketing study commitments. However, PDUFA
provided no resources or new authorities to enable the agency to enforce
that provision. FDA was required to develop and publish a rule on the
reporting format and to report annually on sponsor performance in the
Federal Register. The 2005 Federal Register notice on sponsor progress in
meeting postmarketing study commitments showed that 797 (65 percent)
of New Drug Applications (NDAs) and abbreviated NDA-related post-
marketing commitments are “pending” (they are neither “ongoing” nor
“delayed”) and 47 percent of annual reports on studies that were due were
not submitted to FDA. FDA’s limited authority after marketing and its in-
ability to enforce implementation and fulfillment of important and necessary
postmarketing commitments have been at the core of many proposals for
strengthening FDA’s authority (GAO, 2002b; van der Linden et al., 2003;
Ganslaw, 2005; Grassley, 2005; Thaul, 2005). A recent DHHS Office of
the Inspector General (OIG) report on FDA’s monitoring of postmarketing
commitments noted that FDA has authority to require postmarketing stud-
ies only in certain cases (such as accelerated approval) and that 91 percent
of postmarketing commitments between 1990 and 2004 were requested by
the agency rather than being required by statute or regulation (DHHS and
OIG, 2006). The report also found that postmarketing study commitments
do not have a high priority in FDA, the agency lacks a system for managing
postmarketing study commitments and the existing database of commit-
ments is not consistently populated with information from commitment
letters or from annual status reports, one-third of annual status (required
by FDAMA) reports on postmarketing commitments are not submitted or
are incomplete, and many completed reports lack useful information. The
OIG report also concluded that FDA has no recourse when sponsors do not
make progress or do not report on their commitments (DHHS and OIG,

2006). It is clear that FDA authority to require postmarketing studies (in

cases other than accelerated approval, etc.) is at best unclear, and statutory
change is needed to enable FDA to require such studies when necessary and
appropriate.
Authority to Unilaterally Impose Risk-Reducing Remedies, Such as Label

Changes and Distribution Restrictions
During the drug development process and up to the point of approval,

FDA has a great deal of power. Its communications with sponsors at meet-
ings and in written exchanges (including approval and other letters issued
while an NDA is under review) carry enormous weight; sponsors are highly
motivated to accede to FDA’s requests and demands during this time to
avoid any delay in the approval of their product. After approval, however,
unless a case meets the statutory definition of fraud or misbranding or the
high threshold for proving imminent hazard to the health of the public,
FDA’s regulatory and enforcement options generally lie at the ends of the
spectrum of regulatory actions: do nothing or precipitate the voluntary
withdrawal of the drug. FDA relies on firms to withdraw drugs from the
market voluntarily when safety issues are revealed. Doing nothing implies
not acting on potential threats to the health of the public, and precipitating
withdrawal implies taking the drug from patients who need it, so neither is
a satisfactory option. Currently, most actions involve softer remedies nego-
tiated with a drug sponsor; FDA cannot unilaterally compel label changes,
addition of boxed warnings, or fulfillment of postmarketing study com-
mitments. Nor can it unilaterally restrict marketing, change the content of
a package insert (including Medication Guides), or change the content of
other documents intended for the public. The process of negotiation works
well in many cases, but for some products the process can be long and have
potentially adverse repercussions for safety. The diminished FDA author-
ity after approval is of concern because knowledge of a drug’s risk-benefit
profile is never complete at the time of approval.
FDA takes several approaches to monitoring postmarketing safety.
CDER staff members review Adverse Event Reporting System (AERS) re-
ports using data mining techniques for automated monitoring of the AERS
database, conduct retrospective and observational studies using external
administrative databases, and track the status of phase 4 studies. CDER
Withdrawals are almost always voluntary rather than mandated by FDA. According to its
statute, FDA can institute recalls only for devices and baby formula (Adams et al., 1997).
Medication Guides, or MedGuides, are patient-specific labeling for prescription drug
products determined by FDA to have “serious and significant public health concern requiring
distribution of FDA-approved patient information” (21 CFR 208.1, 4-1-05 Edition, p. 114)
(CDER, 2006).

staff also evaluate and oversee sponsor-designed efforts to manage known

risks, such as developing and implementing RiskMAPs for specific products,
and negotiate with sponsors on actions needed to confirm and address just-
identified risks. Such actions may include additional study, label changes,
and risk communication including Dear Health Professional letters. If safety
problems are identified, FDA can ask the sponsor to propose label language
but cannot require specific language to describe the newly identified risks.
Often, companies argue strongly against label changes, limitation of market-
ing, boxed warnings, and so on.
Regulatory Oversight of Sponsor Promotional Activities
Pharmaceutical companies engage in various activities to promote their

products to the public and to health care providers. Historically, health care
professionals have been the primary target of such promotional activities;
even at the time of this writing, more than 80 percent of promotional bud-
gets are spent on reaching prescribers through such activities as “detailing”
(in-person promotion by sales representatives in the health care setting) and
sponsorship of professional educational opportunities (Rosenthal et al.,
2002). An increasing proportion of promotional funds goes toward DTC
advertising, which is an increasingly contentious area of drug regulation
(GAO, 2002a). In 2006, the United States and New Zealand were the only
nations that permitted DTC advertising of prescription drugs. However, the
European Medicines Agency has for some time considered allowing DTC
advertising for three disease categories (HIV/AIDS, diabetes, and asthma
and other respiratory conditions). (See Box 5-1 for a history of FDA DTCA
regulation.)
Around the turn of the 20th century, some analysts became concerned
that regulation of DTC advertising was not keeping pace with the rapid
evolution in advertising, and the debate that began with the introduction
of DTC advertising became multifaceted (Hunt, 1998). Consumer groups,
insurers, providers, and others have identified several interrelated concerns
about DTC advertising, such as its influence on drug pricing, patient behav-
ior, and prescriber behavior. A 2002 report from the Government Account-
ability Office concluded that DTC advertising appears to increase spending
on prescription drugs and drug utilization (GAO, 2002a). One concern is
that advertising may lead to more rapid uptake of a new drug, which, in
cases where the drug in question is later found to present greater risks than
older drugs in the same class, could potentially dramatically increase the
exposure to that particular drug, even among patients who are not good
candidates for it. That exemplifies the continuing tension between safety
concerns and benefits that outweigh the risks for certain patients. Also, DTC
advertising may distort use patterns within classes of drugs, often driving

use of more costly but no more effective therapies at the expense of older,
cheaper options (e.g., generics).
As a communication or educational tool, DTC advertising appears to
have mixed effects. There is evidence that advertisements have raised aware-
ness about certain health conditions and led people to visit their health
care provider and in some cases, receive needed diagnosis and treatment
(Ostrove, 2000; Calfee, 2002; Aikin, 2003; Almasi et al., 2006) (see Box 5-2
for a sample of public opinion of DTC advertising). Advertisements about
drugs may increase consumer familiarity with products available to treat
their particular condition(s), perhaps empowering them to initiate discus-
sion about therapy with their health care provider, and in some cases, to
alert a less well-informed provider to a particular therapy (Wilkes et al.,
2000; Lyles, 2002; Almasi et al., 2006). On a potentially more negative note,
viewers of television prescription drug advertisements may learn more about
the benefits than about the risks. Also, DTC advertising has been shown to
have an effect on physician prescribing patterns (Aikin, 2003; Mintzes et al.,
2003; Aikin et al., 2005; Weissman et al., 2004; Spence et al., 2005).
FDA’s authority to regulate prescription drug advertisements is found
in Section 502(n) of the FD&C Act, and Title 21 of the Code of Federal
Regulations (CFR) section 202.1 is the source of the implementing regula-
tions that describe the content required in such advertisements (Behrman,
2005). Specifically, regulations require that print advertisements must dis-
close every risk listed in the FDA-approved label as part of a brief summary,
but broadcast advertisements may either contain a brief summary of side
effects and contraindications or make “adequate provision” for conveying
the product’s complete labeling information, that is, a toll-free telephone
number or Web site. FDA can regulate advertising that is false or misleading,
but its regulatory actions must harmonize with First Amendment protec-
tions of truthful commercial speech.
FDA does not have the authority to approve drug advertisements or
require that advertising materials be reviewed prior to their use. The agency
can require and enforce corrective action only after a drug advertisement
has been broadcast (Woodcock et al., 2003). To avoid having to issue a cor-
rection after beginning a marketing activity, a majority of sponsors submit
advertising materials for comment to the CDER Division of Drug Market-
ing and Communication (DDMAC) before airing them (Woodcock et al.,
2003) (see Box 5-3).
The history of court challenges to restrictions on DTC advertising is
lengthy and instructive. Attempts to ban DTC advertising have foundered
due in part to uncertainty as to whether such a prohibition is constitu-
tional. Drug advertising has been held to be commercial speech deserving
First Amendment protection (Virginia State Board of Pharmacy v. Virginia
Citizens Consumer Council, Inc., 425 U.S. 748, 762 [1976]). In Central

BOX 5-1
History of FDA’s DTC Advertising Regulation
As a variety of social changes began to transform the passive patient
into an empowered seeker and contributor of knowledge and information, the
patient-provider relationship and other interactions and spheres of influence
around it changed as well. As early as 1968, FDA developed the first patient
package insert in recognition of the need to instruct patients on the use of a
drug, the inhalational product isoproterenol (Pines, 1999). In the 1970s and
1980s, more health-related information was made available to the general
public (such as the Physician’s Desk Reference), cable television experiment-
ed with physician-oriented channels, and pharmaceutical companies began
to advertise in print to patients. As FDA and the industry reoriented some of
their communication activities to target patients, the agency worked in two dif-
ferent directions: furthering its own role in communicating to patients through
patient package inserts (see Chapter 6) and making determinations about how
to regulate and ascertain the public health implications of emerging industry
promotional efforts directed at consumers (Pines, 1999; DHHS et al., 2005).
FDA’s authority in that respect originates in the FD&C Act, which gave
FDA authority over drug labeling and gave the Federal Trade Commission
(FTC) authority over advertising (Kaplan, 1995). Current statutes give FDA
and FTC overlapping and concurrent authority over the labeling of FDA-
regulated products and over advertising of prescription drugs and devices.
FTC is responsible for regulating false or deceptive claims about products
other than prescription drugs and FDA has primary jurisdiction over false and
misleading labeling of all jointly regulated products and, on the basis of the
definition of advertising as an extension of labeling, over DTC advertising
(Adams et al., 1997; Pines, 1999; Palumbo and Mullins, 2002).
In 1983, FDA requested a voluntary moratorium on all drug advertising to
Hudson Gas & Electric Corp. v. Public Service Commission (447 U.S. 557
(1980)), the Court stated that a governmental restriction upon commercial
speech is lawful only if the asserted governmental interest in the restriction
is substantial, that the speech restriction directly advances the governmental
interest asserted, and that the speech restriction is not more extensive than
is necessary to serve the asserted governmental interest. If the government
cannot demonstrate that it meets all three prongs of the Central Hudson test,
the speech restriction is unlawful. In Thompson v. Western States Medical
Center, 535 U.S. 357 (2002), the Supreme Court applied the Central Hudson
test and ruled that the statutory ban on advertising of compounded drugs

allow the agency to determine where there were adequate statutory protec-
tions for consumers (Palumbo and Mullins, 2002). After its internal decision
making and discussion with academic, consumer, health care, and other
communities, the agency concluded in the Federal Register (1985-Notice 50
FR 36677) that “current regulations governing prescription drug advertising
provide sufficient safeguards to protect consumers.” The notice also stated that
DTC advertising must meet the same requirements as advertising to physi-
cians, including the “brief summary” of risk information required by statute
(21 CFR 202.1).
In the 1990s, as DTC advertising progressed from print to television,
pharmaceutical companies found they could not make product claims in ad-
vertisements, because that required presenting the statutorily “brief summary”
of safety and contraindications information. The television equivalent of the
page of minuscule print on the back of magazine advertisements “would take a
minute or more at a barely readable scrolling rate” (Woodcock et al., 2003). For
this reason, DTC advertisements did not make product claims and generally
consisted of “help-seeking” and “reminder” advertisements. The former de-
scribed an identifiable condition and urged viewers to “see your doctor,” while
the latter mentioned the name of a product without the indication. Advertise-
ments that talked about the disease, but not the drug, or about the drug without
mentioning the indication left viewers confused and led FDA to reconsider the
entire subject of DTC advertising (Pines, 1999). In 1997, FDA produced the
draft Guidance for Industry: Consumer-Directed Broadcast Advertisements.
That document, issued in final form in 1999, allowed television product claim
advertisements, finding that they could meet the statutory requirement and
make “adequate provision” for the information contained in the brief summary
by providing a toll-free number or Web site where consumers could receive
the complete information contained in the drug’s label.
violated commercial speech rights. How the court would react to restric-
tions short of outright ban on DTC advertisements is unclear, but it is worth
noting that in the western states decision the court was unsympathetic to
the argument that DTC advertisements of compounded drugs might affect
physician prescribing practices, to the detriment of their patients. The same
court cases are relevant to whether FDA can require prior approval of the
advertisements. If courts were to conclude that this amounts to a “prior
restraint” on First Amendment protected speech, FDA would have to show
a compelling government purpose for such a policy.
FDA’s regulation of promotional activities was challenged in court by

BOX 5-2
Public Perspectives on DTC Advertising
It has been suggested that DTC advertising is associated with the
transformation in the role of patients from passive to actively contribut-
ing to the health care encounter (shared decision making). A study of
1999 Princeton Survey Research Associates data found that more than
40% of consumers have used DTC advertisement information in their
decision-making process and used information learned from a DTC ad-
vertisement to discuss a prescription drug with their health care provider
(Deshpande et al., 2004). The study also found that consumers believe
advertisements are more effective in communicating benefits than risks
of prescription drugs.
An online survey conducted for the Wall Street Journal in 2005 (Har-
ris Interactive, 2005) found that only 35% of American adults believe FDA
does a good or excellent job in its oversight of DTC advertising. When
asked whether they thought banning DTC advertising for a period of time
after a prescription drug is approved by FDA so “doctors have time to
become familiar with the drug,” 51% agreed. Only 26% of respondents
agreed that banning DTC advertising is not a good idea because “it is how
many patients learn about new treatments that might be right for them.”
the Washington Legal Foundation in 1994. In its lawsuit, the Foundation

claimed FDA had no statutory grounds for regulating companies’ truthful
statements even if they did not adhere to FDA’s requirements for “fair bal-
ance” and “full disclosure.” Although the lawsuit involved off-label promo-
tion to health care providers, the decision against FDA was sweeping and
many believe it limits FDA’s ability to regulate DTC advertising. Washington
Legal Foundation continues to scrutinize FDA’s actions regarding DTC ad-
vertising on First Amendment grounds (FDA, 2002), and in June 2005, the
Foundation launched its “DDMAC Watch,” charging that FDA/DDMAC
requirements exceed the statutory requirement of full disclosure of risks and
that the division does not fully demonstrate how it determines that a given
advertisement is misleading to consumers (Washington Legal Foundation,
2005).
In response to the debate about the effects of DTC advertising on pre-
scription drug use and, ultimately, on drug safety, Senator Frist called for a
2-year moratorium on DTC advertising (Pharma Marketletter July 6, 2005).
The Pharmaceutical Research and Manufacturers of America (PhRMA) is-

sued 15 guiding principles on the advertising of prescription drugs (see Box

5-4). One of the principles called for submitting advertising material to FDA
prior to broadcast, and informing the agency about the intended time of
initial airing. The principles also urged companies to cooperate with FDA
to alter or remove DTC advertising when safety issues about an advertised
prescription drug arise. Twenty-three drug companies agreed to the new
guidelines, and at least two, Bristol-Meyers Squibb and Pfizer, announced
moratoria (for 1 year, and 6 months, respectively) on DTC advertising for
newly approved drugs. That was an important action, and one that is con-
sonant with the committee’s views about the value of limiting marketing of
BOX 5-3
The Division of Drug Marketing and Communication
The CDER office responsible for reviewing DTC advertisements and
other sponsor promotional materials is the Division of Drug Marketing and
Communication (DDMAC). Whether or not an advertisement is reviewed
in a timely manner depends on the resources available for review activi-
ties—DDMAC is small and has limited resources. A forthcoming report
from the Government Accountability Office reviews DDMAC’s work and
resources.
In 2005 the Division’s staff of 35 received 53,000 pieces of promo-
tional material (up from 36,700 in 2002) (Winter, 2005; Woodcock et al.,
2003). When a company submits material, the appropriate DDMAC staff
members (including a social scientist, regulatory counsel, and others)
meet to review the proposed promotional material and make a decision.
“Drugs that are new products, have new indications, are first in a class to
have broadcast advertisements, or are being advertised in a broadcast
medium for the first time have more extensive reviews” (Woodcock et al.,
2003). There are several regulatory tools CDER’s DDMAC can employ
against companies that engage in violative promotional practices. These
include
• Untitled letters (or “notice of violation” letters), requiring sponsors

to discontinue use of false or misleading advertising materials.
• Warning letters, issued to sponsors for more serious violations
than those addressed by untitled letters (i.e., those posing poten-
tially serious health risks to the public).
• Injunctions and consent decrees.
• Referrals for criminal investigation or prosecution.
• Seizures.

BOX 5-4
PhRMA’s 15 Guiding Principles on DTC Advertising (2005)
• Potential public health benefit
• Accurate and not misleading
• Educational
• Identify product as prescription not OTC
• Foster responsible communication between patient and provider
• Educate providers about new medicine or new indication for an ap-
propriate (given all facts about the drug, the condition, etc.) length of
time before beginning DTC advertising
• Working with FDA, alter or discontinue DTC advertising if indicated by
new risk information
• Submit all new DTC TV advertisements to FDA before releasing
them
• DTC TV and print advertisements should inform about non-drug op-
tions (e.g., lifestyle and diet change) when appropriate
• DTC advertisements that identify a product by name should include
indications and major risks
• Design advertisements to present benefits and risks in a balanced,
clear way
• Respect seriousness of conditions and drugs
• Content and placement should be age-appropriate
• Encouraged: promote health and disease awareness as part of DTC
advertising
• Encouraged: include information for uninsured and underinsured
where feasible
new molecular entities in order to prevent potentially rapid uptake of a new

drug about which considerable uncertainty remains.
Rationale for Strengthening Drug Regulation

The “Bully Pulpit” Is Not Enough
A response to the concern about FDA’s limited postmarketing authority

(see Box 5-5 for two interesting exceptions) is that FDA has and can use its
“bully pulpit,” its influence, to compel action on the part of a sponsor. The
committee learned in conversations with and from literature about several
former FDA leaders that even in cases where authority was not clear-cut, the

agency was able to use its bully pulpit to powerful effect in its interactions
with sponsors (IOM Staff Notes, 2005–2006). However, consumer organi-
zations, legislators, scientists, and others who have called for strengthening
and clarifying FDA regulatory authority have provided numerous examples
of cases where the agency was unable to effect desired changes. The com-
mittee asserts that the bully pulpit route leaves potentially critical regulatory
action vulnerable to a subjective and highly variable process of exercising
individual or agency influence, and to the vicissitudes of changing attitudes
toward regulation. That is why FDA’s authorities must be clarified and
strengthened to empower the agency to take rapid and decisive actions when
necessary and appropriate.
BOX 5-5
Two Exceptions in FDA’s Regulatory Authority
Pediatric drugs and accelerated approval drugs provide two impor-
tant incentive mechanisms with which to circumvent the imbalance in
regulatory authority pre- and postapproval, and may be instructive as
models for strengthening the statutory authorities available to FDA. The
FDA Modernization Act of 1997 included patent exclusivity provisions as
an incentive for sponsors who conducted studies of approved drugs in
pediatric populations, and the 2002 Best Pharmaceuticals for Children
Act renewed those incentives. That legislation exemplifies the “carrot”
approach to motivating conduct and completion of studies: no study, no
extended period of exclusivity. The “stick” approach to enforcing study
commitments, which has not worked so well, is illustrated by accelerated
approvals on the basis of surrogate endpoints (e.g., for cancer drugs)
“which allows products to be used in nonresearch clinical care settings
before they have been reliably established to have a favorable benefit-
to-risk profile” (Fleming, 2005). Here again, however, FDA’s authority to
enforce these commitments rests on withdrawing approval if the company
does not complete the requisite studies and the high value of such thera-
peutic agents makes withdrawal undesirable. FDA’s authority to enforce
should be made explicit, as it is for accelerated approvals, and the agency
should also be given additional tools to enforce that authority. The power
to withdraw is not a realistic tool as demonstrated by an FDA study of
8 drugs granted accelerated approvals. The average length of time for
completion of required validation studies was 10 years, and it is unclear
what FDA is able to do if studies are inconclusive (Fleming, 2005).

Approval Should Not Be the “Last Call” for Realistic Regulatory Action
on Safety
In acknowledgement of the complexity of regulatory decision-making,

the multiple conflicting interests involved, and the undesirability of delaying
the approval of important drugs, the committee has sought to recommend
tools that will allow FDA greater regulatory flexibility postapproval and
throughout a drug’s lifecycle. Establishing an interval for reviewing all ac-
cumulated information about new molecular entities (NMEs) will provide
FDA with the authority to take necessary regulatory action when appro-
priate. For most drugs, the review of the drug’s performance for renewal
of approval will be a relatively simple process. For others, the review of
postapproval data will give FDA an opportunity to reconsider the drug’s
risk-benefit profile and respond to safety issues.
Over the years, patient groups and industry representatives have ex-
pressed concern that regulatory actions that are too risk-averse could stifle
innovation in drug development. Longer and larger preapproval trials to
improve certainty about a drug’s risk and benefit at the time of approval
are often not possible, because the extremely broad-based testing in com-
plex populations needed to get a better picture of postapproval use and
risks would slow drug development unacceptably in many disease settings.
Many scientists agree that CDER needs better resources for research and
surveillance and better regulatory tools to manage risk-benefit uncertainty
after approval (Deyo, 2004; Avorn, 2006; Ray and Stein, 2006). In earlier
chapters, the committee described an organizational culture and a scientific
milieu that encourage thinking about and preparing to address postmarket-
ing safety issues much earlier in the development and review process. In this
chapter, the committee calls for strengthening FDA’s authority so that the
point of approval would no longer be the “last call” for major regulatory
action.
The committee finds that FDA’s authority is built on an aging regulatory
framework, that FDA’s largely all-or-nothing regulatory tools limit its ability
to regulate effectively after approval, and that strengthened agency author-
ity would greatly mitigate the concern that fast review and approval may
sacrifice safety. Current enforcement options limit FDA’s ability to regulate
in a manner that matches the agency’s mission—protecting and advancing
the health of the public. FDA’s strongest tools are largely all-or-nothing,
and these are unrealistic options in light of patients’ needs for given drugs.
The agency needs a more nuanced set of tools to respond to uncertainty,
to reduce advertising that drives rapid uptake of new drugs, or to compel
additional studies in the actual patient populations who take the drug after
its approval.

STRENGTHENING FDA’S REGULATORY AUTHORITIES

The committee has examined five areas of regulation in which it believes
that FDA’s authority requires strengthening. The committee reasserts the
importance of a regulatory system that is dynamic and flexible; a key aspect
is that most NDAs and approvals pose few issues of concern and little or no
need for unusual postapproval monitoring and risk management. For most
drugs, the existing interaction between regulator and sponsor is adequate—
incoming safety information does not reveal extremely serious unlabeled ad-
verse events (AEs), and regulatory re-examination (for new indications and
labeling changes) is more or less routine. The committee’s recommendations
for regulatory change apply mainly to what may be a smaller proportion of
drugs—which cannot always be identified beforehand—that have complex
risk-benefit assessments and both lingering and emergent safety concerns.
Possible examples may be found among drugs that are similar to those with
a poor safety record, NMEs with unique modes of action, drugs for which
preclinical testing revealed a potential for clinical safety problems, and so
on. First, clarification or strengthening of existing authority for use postap-
proval is needed to take important regulatory action out of the realm of
negotiation and the bully pulpit. Second, FDA needs a new way to address
DTC advertising that has provoked great interest and debate in recent years.
Third, FDA needs sufficient enforcement tools to ensure that regulatory
requirements imposed at or after approval are fulfilled. Fourth, FDA needs
to develop a major strategy to improve public and health care provider
awareness that approval is not the end of uncertainty and that as new drugs
enter the market, more information about their benefits and risks is likely
to become available. Fifth, regulation of drugs in the United States would
be greatly strengthened by requiring a milestone in each drug’s lifecycle that
triggers a comprehensive review of consolidated safety and efficacy data and
of the status of postmarketing conditions and commitments.
Conditions and Restrictions on Distribution Throughout the Drug

Lifecycle
The committee has found that FDA has some ability to ask for and
egotiate with sponsors about various risk management and other ac-
n
tions. For example, marketing of isotretinoin is conditioned on a four-step
RiskMAP (iPLEDGE) that consists of: registration of and an educational
program for patients, pharmacies, prescribers, and distributors; implemen-
tation of an education program for the four groups just listed; implementa-
tion of a reporting and data collection system for serious AEs in compliance
with statutory requirements and as pertaining to the sale and dispensing
of isotretinoin outside the iPLEDGE program; and implementation of a

plan to monitor and minimize drug exposure during pregnancy through a

pregnancy registry (Houn, 2006). It must be noted here that the iPLEDGE
program has drawn criticism from providers and patients who find its
requirements onerous and the administration of the program inadequate
(Ritter, 2006). In another example, FDA issued a public health advisory
pertaining to the multiple sclerosis drug natalizumab after an unexpected
serious AE surfaced. The sponsor later withdrew natalizumab from the
market and began working with CDER staff to develop a risk management
program (including restricted distribution through certified infusion centers
and so on). FDA convened the appropriate advisory committee to review the
sponsor’s proposed risk management program and CDER’s evaluation of it.
The advisory committee recommended that natalizumab be returned to the
market with the necessary safeguards; after additional FDA consideration,
Tysabri was returned to the market in July 2006. Another important ex-
ample is clozapine, an antipsychotic whose use was conditioned on regular
blood work showing that agranulocytosis, a potentially fatal side effect of
the drug, was not emerging. Even more recently, FDA suggested 5-year fol-
lowup of patients on the HIV drug class of CCR5 antagonists, which target
a novel pathway and pose a serious risk of worsening the disease.
The committee believes that although FDA is able to negotiate for label
changes (including warnings), and to impose restrictions or conditions on
distribution at approval, it exercises those options inconsistently and lacks
both the ability to require sponsor agreement with label changes and com-
pliance with conditions imposed after approval and enforcement threats
short of withdrawal. The conditions on the distribution of isotretinoin
were implemented at the conclusion of an extremely long process. Label
change negotiations for some drugs with emergent safety problems (such as
cisapride, rofecoxib) have been unreasonably drawn out, and sponsors have
made great effort to soften the language preferred by FDA (Harris and Koli,
2005). Such delays and barriers to timely action are problematic given the
seriousness of the AEs which such label changes and similar measures are
intended to warn about and to prevent (Kweder, 2004).
FDA’s regulatory authorities do not give the agency sufficient flexibility
to address safety concerns quickly during a drug’s lifecycle and as consistent
with the agency’s public health mission. No drug is thoroughly understood
at the time of approval, but most drugs perform effectively and without
major safety concerns once they are on the market. FDA needs more a con-
sistent approach and more nuanced range of enforcement measures to act
when an approved drug’s risk-benefit profile is in question and when safety
concerns arise after marketing.
FDA needs new authority or a clarification of existing authority to apply
restrictions and conditions on distribution from the regulatory “tool kit”
described below. Some of the regulatory options described have already

been used in some cases, but are often exercised at the point of approval.
In general, even if FDA is successful in placing a condition or restriction at
the time of approval, doing so after marketing is substantially more chal-
lenging. For example, FDA’s authority over labels is limited to approving
the contents of a label prepared by the sponsor, after a sometimes lengthy
process of negotiation about the language. Although FDA may disagree with
the sponsor and request certain changes, it is the committee’s understanding
that the agency cannot compel the sponsor to make changes.
5.1: The committee recommends that Congress ensure that the

Food and Drug Administration has the ability to require such
postmarketing risk assessment and risk management programs as
are needed to monitor and ensure safe use of drug products. These
conditions may be imposed both before and after approval of a
new drug, new indication, or new dosage, as well as after identifi-
cation of new contraindications or patterns of adverse events. The
limitations imposed should match the specific safety concerns and
benefits presented by the drug product. The risk assessment and
risk management program may include:
a. Distribution conditioned on compliance with agency-initiated

changes in drug labels.
b. Distribution conditioned on specific warnings to be incorporated
into all promotional materials (including broadcast direct to
consumer [DTC] advertising).
c. Distribution conditioned on a moratorium on DTC
advertising.
d. Distribution restricted to certain facilities, pharmacists, or physi-
cians with special training or experience.
e. Distribution conditioned on the performance of specified medical
procedures.
f. Distribution conditioned on the performance of specified ad-
ditional clinical trials or other studies.
g. Distribution conditioned on the maintenance of an active adverse
event surveillance system.
As with any grant of regulatory authority, FDA authority to revise

labels, require conditions on distribution, and to impose penalties must
be accompanied by administrative procedures that protect the due process
rights of affected parties. These procedures, as generally used throughout
federal law, include adequate notice, opportunity for response, and avenues
of appeal within the agency and, typically, with the courts. In this fashion,
statutory authority to impose restrictions and remedies is neither dictato-

rial nor unlimited. It does, however, provide the FDA with a wider range
of remedies and a stronger base from which to negotiate voluntary actions,
while still providing affected parties an avenue of relief from what they may
perceive as unwarranted or overly burdensome actions.
The committee also finds that FDA needs enforcement tools to ensure
that the regulatory requirements described above are applied and met.
Specifically, FDA does not have the set of flexible regulatory actions that
it needs to enforce necessary and important postmarketing commitments
effectively.
5.2: The committee recommends that Congress provide oversight

and enact any needed legislation to ensure compliance by both the
Food and Drug Administration and drug sponsors with the provi-
sions listed above. FDA needs increased enforcement authority and
better enforcement tools directed at drug sponsors, which should
include fines, injunctions, and withdrawal of drug approval.
The agency’s timely performance of the required postmarketing safety

reviews could be listed as one of the goals associated with PDUFA and re-
ported on in the goals letter to Congress (see Chapter 3).
A Symbol to Denote Limited Knowledge About New Drugs
A recurring theme in this report is the committee’s concern that the

public and even health care providers may base their choices and behaviors
related to prescription drugs on inaccurate assumptions. For example, there
may be a lack of general awareness that FDA approval does not represent a
lifetime guarantee of safety or the end of uncertainty, that the understanding
of a drug’s risk-benefit profile evolves over the drug’s lifecycle, and that new
drugs are approved on the basis of carefully controlled limited testing in
relatively small populations and under circumstances that may differ greatly
from a drug’s use after marketing.
The committee believes that a symbol or icon could be added to the la-
bels and all materials associated with new drugs, new combinations of active
substances, and new delivery systems to alert patients and the general public
that such products are new and that the knowledge available about their
performance is often incomplete. In the United Kingdom, a black triangle
marks every newly marketed drug approved by the Medicines and Health
products Regulatory Agency (MHRA). The black triangle signifies that a
pharmaceutical product is under intense scrutiny of regulatory authorities,
and the symbol is placed next to the product name in the British National
Formulary and in the British pharmaceutical industry’s compendium of

drugs approved for marketing (MHRA, 2006). The black triangle program
has an additional purpose of alerting National Health Service providers to
report all adverse reactions (rather than only serious ones) associated with
drugs labeled with the symbol. Study of reporting patterns indicates that
despite the request for both serious event and non-serious event reporting,
providers are five times more likely to report a serious than a non-serious
adverse drug reaction (Heeley et al., 2001). Therefore, it is not clear whether
the black triangle program in the United Kingdom was successful in increas-
ing provider reporting. However, the black triangle was not intended as a
tool to inform or educate consumers, so evidence from the United Kingdom
would not necessarily be informative in the case of a somewhat different
use for such a symbol. The committee believes that marking the label and
all promotional material for newly approved drugs or indications with a
special symbol and communicating its meaning to patients and consumers
may help to increase awareness of the nature of newly approved therapies,
for example, the incompleteness of information on safety.
5.3: The committee recommends that Congress amend the FD&C

Act to require that product labels carry a special symbol such as
the black triangle used in the United Kingdom or an equivalent
symbol for new drugs, new combinations of active substances, and
new systems of delivery of existing drugs. The FDA should restrict
direct-to-consumer advertising during the period of time the special
symbol is in effect.
The symbol should remain on the drug label and related materials for
2 years unless FDA chooses to shorten or extend the period on a case-by-
case basis. The committee believes that companies should refrain from DTC
advertising during the black triangle period, and would favor imposition of
a formal moratorium on such advertising. Such restraints may be necessary
because DTC advertising has the ability to dramatically increase the uptake
of a newly approved drug. In some cases, that may expose larger numbers
of people (compared with a lower-key market introduction) to a new drug
with not-yet-documented safety concerns. Recognizing the legal uncertain-
ties surrounding such an imposition, the committee suggests that at the very
least any DTC advertising during this period should include explicit notice
that the data related to risks and benefits associated with the product are
less extensive than those related to alternative products that have been in
use for a longer period and should include a caution to speak to one’s health
care provider about alternatives. If a moratorium on DTC advertising for
the time that the special symbol is in effect is deemed to be inconsistent with
First Amendment protections of commercial speech, the committee believes

that it is necessary to require placement of the symbol on all promotional

materials, patient or consumer information, and all DTC advertising while
the special symbol is in effect.
Products carrying the special notation also would be subject to height-
ened postmarketing scrutiny, with measures that include:
• Prompt review of individual 15-day reports of AEs (sponsors are

required to report serious, unexpected AEs to the agency within 15
calendar days) in addition to review of regular tabulations of such
reports.
• Followup of these reports as needed to obtain additional informa-
tion, such as that on related health factors and resolution of AEs,
that may be helpful in assessing role of product and overall impact
of AEs.
• Scheduling of regular meetings of postmarketing and premarket re-
viewers at which summaries of recent reports of AEs related to newly
approved products prepared by the postmarketing reviewers would
be discussed.
• Preparation of annual summaries of reports received on new prod-
ucts to be posted on the FDA Web site—not simply a list or tabula-
tion, but a thoughtful interpretation of the reported experiences and
what they mean for continued use of the drug.
The committee believes that a broad-based discussion of the most ap-

propriate symbol for a US audience would be desirable before the program
is launched, and an evaluation of the effect of such a program on public
awareness and knowledge would be important.
Periodic Review of Data on New Molecular Entities
In 1977, the Review Panel on New Drug Regulation found that “FDA
even lacks a basis for judging whether the approved drug and the approved
labeling are still correct, since there is no comprehensive system for gath-
ering and utilizing data on an approved drug’s performance and effect”
(Department of Health Review Panel on New Drug Regulation, 1977:91).
This continues to be the case.
The committee finds that a lifecycle approach to risk and benefit would
be facilitated by establishing a milestone in a drug’s lifecycle for a compre-
hensive review of consolidated safety and efficacy data and the status of
postmarketing conditions and commitments (see Chapter 4 for discussion of
the assessment of risks and benefits). There is no systematic CDER review of
Refer to the Code of Federal Regulations, 21 CFR 314.80.

accumulated knowledge about a drug a year or more after its approval for
marketing. In 2005, the European Medicines Agency enacted a new statute
requiring that prescription drug marketing authorizations in the European
Union be reviewed and, if appropriate, renewed at 5 years after initial ap-
proval (EMEA, 2005).
5.4: The committee recommends that FDA evaluate all new data
on new molecular entities no later than 5 years after approval.
Sponsors will submit a report of accumulated data relevant to
drug safety and efficacy, including any additional data published
in a peer-reviewed journal, and will report on the status of any
applicable conditions imposed on the distribution of the drug called
for at or after the time of approval.
As described above, such conditions on distribution may include a

moratorium on DTC advertising, postmarketing studies, monitoring (such
as registries, active surveillance, and so on), and restricted distribution. The
5-year report would include results of postmarketing studies, outcomes of
monitoring, and, where applicable, the extent of DTC advertising (examples
of all advertisements and total expenditure) during the first 5 years. For most
drugs, the committee expects the 5-year “review” process to entail nothing
more than a one-page FDA letter agreeing with the sponsor’s summary of
all accumulated (or consolidated) safety and efficacy information. On rare
occasions, as a consequence of the review, regulatory action including sus-
pension or withdrawal of approval (for example, if evidence of imminent
public health hazard emerged in the course of the review) would be a pos-
sibility. This recommendation is not intended to preclude any regulatory
action, and it does not constitute a request for new authority for FDA,
rather, for the creation of a milestone moment in a drug’s lifecycle that
would allow FDA to review what has been learned during a drug’s first 5
years on the market.
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Communicating About Safety
“Information is ultimately what permits people to make meaningful choices

about whether or not to take new drugs” (Greenberg, 2003).
“1962—Consumer Bill of Rights is proclaimed by President John F. Kennedy in

a message to Congress. Included are the right to safety, the right to be informed,
the right to choose, and the right to be heard” (FDA Milestones).
Patients use the medications approved by the Food and Drug Adminis-
tration (FDA) and prescribed by health care providers. Despite that, patients
historically have been left out of the loop in much of the communication that
has occurred among the biomedical research, health care, and pharmaceuti-
cal enterprises and government regulators. As described in Chapter 1, social
and technological changes have transformed the practice of medicine, the
role of patients, and the information environment that surrounds patients
and physicians and influences their interactions (Henwood et al., 2003).
Public interest in and knowledge about drugs have also evolved greatly due
to direct-to-consumer (DTC) prescription drug advertising, ever wider In-
ternet and e-mail access and breadth of information, a shift in the formerly
passive role of patient, and the emergence of a powerful patient advocacy
movement (Atkin and Wallack, 1990; Dupuits, 2002; Pew Internet and
American Life Project, 2003, 2004, 2005). Finally, the recent safety concerns
about widely used, well-known drugs and drug classes, from antidepres-
sants to anti-inflammatory drugs, have further mobilized public interest in
drug safety issues. As noted earlier, FDA, the pharmaceutical industry, the
health care delivery system, and other stakeholders have begun to grapple
with serious questions about when to inform patients and consumers about
risk, how to communicate effectively, and what information is needed for
personal health, health care system, and regulatory decision making.
This chapter is intended not to provide a comprehensive assessment of
communication issues in the drug system but rather to describe briefly major
http://www.fda.gov/opacom/backgrounders/miles.html.
177

communication efforts at FDA, discuss some of the challenges that have

complicated those activities, and to suggest two specific areas for improve-
ment and makes appropriate recommendations.
Pharmaceutical products constitute 11 percent of the health care dollar
(Smith et al., 2005). They are characterized by complex risk-benefit profiles,
long and complicated research processes, and high visibility. They have the
potential to provide important health benefits, from reducing risk of death
to improving quality of life, and they are subject to extensive regulatory
oversight. Those are some of the reasons why effective and timely risk com-
munication about drugs is essential.
Roles and Needs of Providers and Patients

Despite the greater role patients play in their own health care, and the
health care delivery system’s recognition of that role, most of the commu-
nication “transactions” in the drug safety system occur among regulators,
sponsors, providers, and payors. There are two types of information that
may be communicated: information directed outward from stakeholders in
the drug safety system (such as education, risk communication, promotional
information), and information directed toward the drug safety system from
those who experience drug safety problems directly or indirectly (including
drug event reporting by patients or providers).
Communication Between the Public and the Drug Safety System
The Committee on the Assessment of the Drug Safety System did not
endeavor to conduct a comprehensive examination of the communication
needs of patients and the general public. Another IOM committee addressed
these issues extensively in their report, Preventing Medication Errors (2007).
That report recommended specific steps the health care delivery system,
FDA, and other federal agencies could take to improve the availability, ac-
cessibility, quality, and quantity of patient and consumer information about
drugs and their risks and benefits (see Box 6-1 and Appendix A). The present
chapter focuses only on two areas where the committee believes FDA could
strengthen its programs targeting patients’ and consumers’ communication
needs.
Consumers and patients seek to access the information they need about
the drugs they use through an incomplete and imperfect patchwork of
sources (Brann and Anderson, 2002). These sources are of varying reliability
and usefulness, and they include health care providers and pharmacists,
DTC advertising, printed information made available by pharmacies, FDA-
required patient package inserts for a limited number of drugs, informa-
tion from a wide variety of sources made available on the Internet, and so

COMMUNICATING ABOUT SAFETY 179
on. Providers develop their knowledge about prescription drugs through

a variety of means, including journal articles, interactions with company
sales representatives, continuing education, professional associations, com-
munication or education provided by their practice, hospital, or health
system, and communiqués from FDA (either direct for those who request
FDA electronic communications, or through professional associations that
subscribe to or relay FDA’s public health advisories).
FDA communicates to the public and to providers about drug safety
concerns through public health advisories and warning. Some components
of FDA’s risk communication are under development, as described in Ap-
pendix A. For example, the agency has established a Drug Watch Web site
intended for timely communication of safety issues to the public, but con-
cerns arose about communicating complex issues of scientific uncertainty,
explaining complex data clearly and in a way that is useful to patients (FDA,
2005). At the time of this writing, the committee had not yet learned of a
resolution of these issues.
FDA has historically focused most of its communication activities on
health care providers who prescribe FDA-approved drugs and serve as
the “learned intermediary” between drug production and regulation and
patients. That is evident in the dense, technical language of prescription
drug labeling rules. In recent years, FDA has acknowledged the impor-
tance of communicating with and to patients and the general public by
including them in its mission, which calls for “advancing the public health
by . . . helping the public get the accurate, science-based information they
need to use medicines and foods to improve their health.” FDA has also
reoriented some of its information and communication toward patients and
the public, and has held several public hearings on issues related to com-
munication and DTC advertising.
At least three types of the Center for Drug Evaluation and Research
(CDER) regulatory activities involve communication-related activities per-
tinent to patients and the public. First, FDA has authority over prescription
drug advertising developed and published or broadcast by sponsors, and
CDER’s Division of Drug Marketing and Communication sends untitled
letters and warning letters to sponsors whose advertisements do not convey
a fair balance of risk and benefit information. Second, all of FDA’s advisory
committees include consumer representatives. Those committees’ meetings
are open to the public and routinely include opportunity for public comment
on the issues under discussion. Some committee meetings may address risk
communication issues. Third, FDA provides information about prescrip-
tion drugs and other FDA-approved therapies on its Web site, and in print
information about prescription drugs in general on a very small scale.
See Chapter 5 for explanation.

BOX 6-1
Recommendations Pertaining to Consumers from
Preventing Medication Errors
Recommendation 1: To improve the quality and safety of the medication-use
process, specific measures should be instituted to strengthen patients’ capaci-
ties for sound medication self-management. Specifically:
• Patients’ rights regarding safety and quality in health care and medi-
cation use should be formalized at the state and/or federal levels and
ensured at every point of care.
• Patients (or their surrogates) should maintain an active list of all
prescription drugs, over-the-counter (OTC) drugs, and dietary supple-
ments they are taking; the reasons for taking them; and any known
drug allergies. Every provider involved in the medication-use process
for a patient should have access to this list.
• Providers should take definitive action to educate patients (or their
surrogates) about the safe and effective use of medications. They
should provide information about side effects, contraindications, and
how to handle adverse reactions, as well as where to obtain additional
objective, high-quality information.
• Consultation on their medications should be available to patients at
key points along the medication-use process (during clinical decision
making in ambulatory and inpatient care, at hospital discharge, and at
the pharmacy).
Recommendation 2: Government agencies (i.e., the Agency for Healthcare

Research and Quality [AHRQ], the Centers for Medicare and Medicaid
Services [CMS], FDA, and the National Library of Medicine [NLM]) should
enhance the resource base for consumer-oriented drug information and
The Role of Other Government Agencies
Other agencies in the Department of Health and Human Services

(DHHS), such as the Agency for Healthcare Research and Quality (AHRQ),
the National Institutes of Health (NIH), and the Centers for Medicare and
Medicaid Services play a role in public communication about drug risk and
benefit. For example, AHRQ’s Effective Health Care Program develops
consumer summaries of reports prepared by its DEcIDE (Developing Evi-
dence to Inform Decisions about Effectiveness) network—prescription drug
outcomes are one focus of the network—and other material on evidence-
based practice. NIH conducts or sponsors clinical trials and does make

medication self-management support. Such efforts require standardization of

pharmacy medication information leaflets, improvement of online medication
resources, establishment of a national drug information telephone helpline, the
development of personal health records, and the development of a national
medication safety dissemination plan.
• Pharmacy medication information leaflets should be standardized to

a format designed for readability, comprehensibility, and usefulness to
consumers. The leaflets should be made available to consumers in a
manner that accommodates their individual needs, such as those as-
sociated with variations in literacy, language, age, and visual acuity.
• NLM should be designated as the chief agency responsible for Internet
health information resources for consumers. Drug information should
be provided through a consumers’ version of the DailyMed program,
with links to NLM’s Medline Plus program for general health and ad-
ditional drug information.
• FDA, CMS, and NLM working together should undertake a full evalu-
ation of various methods for building and funding a national network
of drug information helplines.
• CMS, FDA, and NLM should collaborate to confirm a minimum data set
for personal health records and develop requirements for vendor self-
certification of compliance. Vendors should take the initiative to improve
the use and functionality of personal health records by incorporating
basic tools to support consumers’ medication self-management.
• A national plan should be developed for widespread distribution and
promotion of medication safety information. Health care provider,
community-based, consumer, and government organizations should
serve as the foundation for such efforts.
SOURCE: IOM (2007).
public announcements about major health findings from them, good and
bad. Recent studies from the Women’s Health Initiative have generated such
communications (e.g., about the benefits and risks of Hormone Replacement
Therapy) in postmenopausal women. Through NLM, NIH also operates the
clinicaltrials.gov trial registration Web site (discussed in Chapter 4).
Communicating Between Providers and the Drug Safety System
Although the present report acknowledges general areas of opportunity

and challenges, it does not discuss the communication roles and needs of

providers in great detail. The IOM report Preventing Medication Errors

(2007) describes challenges in this area, including barriers to implementing
and perfecting the use of information technology. That report also recom-
mends several measures to improve communication to providers by govern-
ment agencies and health systems (see Box 6-2 and Appendix C).
In the health care delivery system, information about drug safety, and
particularly risk management, is integrated into drug prescribing and dis-
tribution systems (e.g., claims databases that issue alerts when two drugs
with potential interactions are prescribed for the same patient). In its work,
BOX 6-2
Recommendations Pertaining to Providers (and Patients) from
Recommendation 3: All health care organizations should immediately make
complete patient-information and decision-support tools available to clinicians
and patients. Health care systems should capture information on medication
safety and use this information to improve the safety of their care delivery
systems. Health care organizations should implement the appropriate systems
to enable providers to:
• Have access to comprehensive reference information concerning

medications and related health data.
• Communicate patient-specific medication-related information in an
interoperable format.
• Assess the safety of medication use through active monitoring and
use these monitoring data to inform the implementation of prevention
strategies.
• Write prescriptions electronically by 2010 and all pharmacies to be
able to receive them electronically, also by 2010. All prescribers should
have plans in place by 2008 to implement electronic prescribing.
• Subject prescriptions to evidence-based, current clinical decision
support.
• Have the appropriate competencies for each step of the medication
use process.
• Make effective use of well-designed technologies, which will vary by
setting.
Recommendation 5: Industry and government should collaborate to es-

tablish standards affecting drug-related health information technologies,
specifically:

the committee learned about a wide variety of communication opportunities

and challenges related to involving the general public and disease groups
(such as online support groups) in reporting drug-related adverse events,
about a movement to counteract commercial pharmaceutical company
“detailing” with neutral “academic detailing” (Avorn, 2005), about First
Amendment-based opposition to calls for increased FDA regulation (includ-
ing banning) of DTC advertising, etc.
Providers, including physicians and pharmacists, are encouraged to
report adverse drug reactions experienced by their patients to the manufac-
• The NLM should take the lead in developing a common drug nomen-
clature for use in all clinical information technology systems based on
the standards for the national health information infrastructure.
• AHRQ should take the lead in organizing safety alert mechanisms by
severity, frequency, and clinical importance to improve clinical value
and acceptance.
• AHRQ should take the lead in developing intelligent prompting mecha-
nisms specific to a patient’s unique characteristics and needs; provider
prescribing, ordering, and error patterns; and evidence-based best-
practice guidelines.
• AHRQ should take the lead in developing user interface designs based
on the principles of cognitive and human factors and the context of the
clinical environment.
• AHRQ should support additional research to determine specifications
for alert mechanisms and intelligent prompting, and optimum designs
for user interfaces.
Recommendation 7: Oversight and regulatory organizations and payers

should use legislation, regulation, accreditation, and payment mechanisms
and the media to motivate the adoption of practices and technologies that
can reduce medication errors, and to ensure that professionals have the com
petencies required to deliver medications safely.
• Medication error reporting should be promoted more aggressively by

all stakeholders (with a single national taxonomy used for data storage
and analysis).
• Accreditation bodies responsible for the oversight of professional
education should require more training in improving medication man-
agement practices and clinical pharmacology.

turer or to FDA’s Adverse Event Reporting System (providers may report

through the MedWatch portal). Although proposals have been made in
the United States and Europe to mandate provider reporting, there is little
evidence that such attempts would be successful. Furthermore, spontane-
ous reporting is only one component of an effective drug safety surveil-
lance program, and should not be relied on as the sole or primary source
of information. Finally, the quality of spontaneous reports is an important
concern; a large quantity of incomplete and poorly executed reports would
be unhelpful.
How Industry Communicates to the Public and Patients

The frequently dangerous patent medicines that led to the Pure Food
and Drugs Act of 1906 and the Food, Drug, and Cosmetic Act of 1938 were
advertised directly to consumers with their colorful labels and claims, but
modern prescription drugs, as products of biomedical science are promoted
largely to health care providers, mostly to physicians. About 86 percent
of industry promotional budgets still pay for “sampling” (providing free
samples to providers), detailing (drug promotion to individual providers),
and advertising in professional journals (Kaiser Family Foundation, 2004).
However, the 1980s were a period of increased advertising directed at pa-
tients, known in some contexts as consumers—the term intended to reflect
the changing role of patients to more active engagement with the health care
system and involvement in their own health care. In 2005, pharmaceutical
manufacturers spent an estimated $4.2 billion on DTC advertising (and
$7.2 billion on professional promotion through journal advertising and sales
representative contacts) (IMS Health, 2006). A more recent development in
pharmaceutical promotion is relationship marketing, in which companies
customize their promotional and informational efforts to target patients
who have specific diseases, such as diabetics who use a specific product
(Ahearne et al., 2005).
FDA’s Challenges in Communicating to the Public and Patients

FDA faces a number of challenges in improving its internal and external
communication. As noted in Chapters 1 and 3, CDER has recognized that
its credibility can be compromised by adverse publicity with respect to drug
The mention of the term consumer is not intended to reflect the committee’s views on its
validity. The committee is aware of the favorable sides of health consumerism—such as em-
powerment and self-management—and of the more unfavorable aspects, including the com-
modification of health. It is also aware of the reality that access to health care and the level of
health literacy (IOM, 2005) determine whether a patient has the opportunity to make health
care choices and to form productive relationships with health care providers.

BOX 6-3
FDA Response to the December 2005 Public Meeting Input
In December 2005, FDA held a public hearing on communication of
drug safety information. The hearing was intended to facilitate discussion
on FDA’s risk communication with health care providers and patients/
consumers. The following topics presented to FDA at the meeting were
noted as needing improvement and attention:
• Engaging health care professionals.

• Improving Internet access for patient information.
• Maintaining benefit-risk balance in communications.
• Standardizing one-way communications.
• Addressing needs of those with low health literacy and poor
English-language skills.
safety, and it has made efforts to improve transparency and communication,

including establishing the Drug Watch Web site (currently under discussion
by the agency), charging its recently constituted Drug Safety Oversight
Board (DSB, discussed in Chapter 3) with (among other things) oversight
of external communication, and creating a new Office of Safety Policy and
Communication. However, the guidance document on the purpose and
functioning of the Drug Watch Web site is being reconsidered because of
concerns about needlessly alarming the public and about releasing safety
data without proper context and analysis (DHHS et al., 2005a,b; personal
communication, S. Cummins, FDA, 2006). Representatives of consumer
organizations that participated in the December 2005 hearing on drug safety
communication told the agency about their concerns and criticisms of the
FDA Web site and offered specific suggestions for improving it and making
it more user-friendly and broadly accessible (see Box 6-3).
Consumer Medication Information
It may surprise many Americans to know that most prescription drugs

have only a physician package insert and lack patient package inserts (also
known as patient information leaflets), which provide information about a
drug’s use, risks, and benefits in clearer, more accessible language appropri-
ate for a lay reader (IOM, 2007). The types of patient package information
required by FDA to accompany dispensed drugs include information on oral
contraceptives and estrogens (required since 1968 by regulation, 21 CFR

310.501 and 310.515, respectively) and medication guides (MedGuides),

which are developed by sponsors (and approved by FDA) from the label text
for several hundred drugs that “pose serious and significant public health
concern” (CDER, 2006). When patients receive what FDA calls consumer
medication information it is in the form of a leaflet developed by health care
organizations, or more likely, content included by pharmaceutical software
providers with the software that they sell to pharmacies. Sponsors may also
choose to prepare patient package inserts, which requires FDA approval.
Until 1996, there were no standards and no requirements for the minimal
useful information to be provided in patient leaflets.
In 1979 and 1980, FDA published in the Federal Register the draft, and
then the final rule requiring written patient information for prescription
drugs (CDER and CBER, 2006). The draft rule addressed all prescription
drugs, but the final focused only on a limited number of prescription drugs.
In 1982, FDA revoked those regulations, partly in response to assurances
by the pharmaceutical industry, by health care professional organizations,
and private-sector developers of medication information that the objectives
of the final rule would be better achieved without regulation.
The absence of FDA-approved literature on some drugs that are on the
market has been criticized by consumer advocates and other parties, and it
seems to be a result of legislative obstacles due to private-sector resistance,
long-standing claims that regulation in this regard might interfere with the
practice of medicine and pharmacy, and finally, FDA’s lack of resources.
According to the current deputy commissioner for operations, “the Agency
[in 1980] published a rule requiring FDA approved patient labeling for ten
drugs/drug classes,” with the expectation that this would be extended to
all prescription drugs. In 1982, “the rule was revoked in favor of private
sector efforts to provide patient information that FDA would monitor”
(Woodcock, 2002). In 1996, Congress opted to leave consumer medication
information in the hands of private-sector content providers and instead
tasked FDA with oversight to ensure that 95 percent of consumer medica-
tion information meets quality standards by 2006. The quality standards
were defined by a broad consortium, the Steering Committee for the Col-
laborative Development of a Long-Range Action Plan for the Provision of
Useful Prescription Medicine Information, which was established to develop
an action plan for the secretary of DHHS in 1996. FDA expects to complete
its review of the quality of consumer medication information in 2007 (see
Box 6-4).
FDA uses the term labeling to refer to any FDA-approved materials based on the formal
label on which FDA and the sponsor agree at the time on approval or to change in the label
after marketing.
The action plan is available online at http://www.fda.gov/cder/offices/ods/keystone.pdf.

BOX 6-4
Criteria for Useful Consumer Medication Information
Written prescription medicine information should be
(1) scientifically accurate
(2) unbiased in content and tone
(3) sufficiently specific and comprehensive
(4) presented in an understandable and legible format that is readily
comprehensible to consumers
(5) timely and up-to-date
(6) useful
SOURCE: Steering Committee for the Collaborative Development of a Long-Range

Action Plan for the Provision of Useful Prescription Medicine Information (1996).
One function of the DSB (described in more detail in Chapter 3), now
located in the Office of Safety Policy and Communication, is to produce
patient information sheets for every drug, to be posted on the FDA/CDER
Web site. The sheets are intended to provide safety alerts and other emerging
information to consumers about specific drugs. However, a footnote to the
Drug Watch guidance developed by CDER seems to suggest that the center’s
long-term goal is to develop patient information sheets (and provider sheets)
for every drug on the market (FDA, 2005; Galson, 2005; confirmed by
S. Galson, personal communication, February 22, 2006).
Improving Communication with the Public
CDER uses the expertise of 17 advisory committees (and the Drug

Safety and Risk Management advisory committee) charged with advising
FDA and the center on issues related to broad classes of drugs (such as onco-
logic, cardiovascular, and renal). Although communication issues related to
specific drugs may emerge in the committees’ work, the existing committees
are chartered to review and evaluate safety and efficacy data (on marketed
or investigational human drug products) and to make recommendations to
the agency. The committee has found a 1996 reference to an FDA Com-
mittee on Patient Education (1996). To our knowledge, there is no advisory
http://www.fda.gov/cder/audiences/acspage/index.htm.

committee devoted to advising the agency (and CDER specifically) on public

communication issues that arise during the lifecycle of drugs.
The committee remains perplexed about the tasks of the new DSB,
and how they relate to the center’s other plans for improving communica-
tion. The DSB, discussed in Chapter 3, has the dual purpose of addressing
disagreements among CDER offices or divisions and assisting the center
in communicating about drug safety issues to patients (Meadows, 2006;
Throckmorton, 2006). As the committee noted in Chapter 3, assigning the
two functions to the same internal body may not be effective. Both sets of ac-
tivities require substantial expertise and resources, and from a management
point of view, it seemed unusual that the two functions would be assigned
to the same group. Although the committee realizes that the appearance of
internal CDER conflict over how drug safety issues are identified, defined,
and addressed became associated in the press with poor and delayed com-
munication to the public about those drug safety issues, the committee
believes that these two areas should be managed separately. Also, the DSB
does not possess substantial expertise in the area of risk communication
and consumer or patient behavior. For these reasons, the committee believes
that a separate, external entity is needed to advise the agency on the diverse
communication needs of the public and patients and on the best evidence
on risk communication tools and strategies.
Several FDA centers, including CDER, the Center for Biologics Evalu-
ation and Research (CBER), and the Center for Devices and Radiological
Health (CDRH), share similar communication challenges. An advisory com-
mittee on consumer and patient communication issues could have a dual
function, serving as a conduit for public input into FDA’s decision making
(for example, through surveys), and an advisor to the agency on a range of
communication issues. Other government agencies have advisory commit-
tees that involve consumers and patients (see Box 6-5).
The presence of consumer representatives in FDA’s advisory committee
process is limited to one member per committee, and communication issues
understandably constitute just a small component of advisory committees’
work. We believe that the agency, and especially CDER, would benefit from
having a new advisory committee focused entirely on communication with
the public, including risk communication. Public communication issues cut
across CDER, CBER, and CDRH such as when and how to warn, how and
what to communicate, so the proposed committee should serve all relevant
centers.
6.1: The committee recommends that Congress enact legislation

establishing a new FDA advisory committee on communication
with patients and consumers. The committee would be composed
of members who represent consumer and patient perspectives and

organizations. The advisory committee would advise CDER and

other centers on communication issues related to efficacy, safety,
and use during the lifecycle of drugs and other medical products,
and it would support the centers in their mission to “help the public
get the accurate, science-based information they need to use medi-
cines and foods to improve their health.”
The proposed advisory committee should also have the role of devel-
oping and implementing a comprehensive consumer information program
at FDA. The expertise needed on the advisory committee may include
consumer and patient perspectives (adult, children, chronic conditions,
new reader, consumer organizations, disease specific advocacy groups, and
patient safety advocacy groups), risk communication, health literacy, social
marketing expertise, public relations expertise, social sciences expertise with
an emphasis on qualitative research and survey science, journalism, and eth-
ics. The advisory committee could develop standards for effective commu-
nication of risk and benefit information, patient-provider communication,
and patient participation in the generation of drug safety information and
data, and apply available expertise and evidence to refine the structure and
content of public health advisories, develop more robust standards for FDA’s
assessment of DTC advertising. It would, like all other advisory committees,
be based in the Office of the Commissioner, but it would work closely with
the new CDER Office of Safety Policy and Communication.
The scope of work for the new CDER Office of Safety Policy and Com-
munication is still under development. Given the reactive, fragmentary,
and short-lived nature of previous CDER initiatives and organizational
changes, the committee believes that special attention and commitment
will be required to allow the new office to succeed. It will be essential to
have its scope and goals clearly defined, and for its work to be given a high
priority in CDER.
6.2: The committee recommends that the new Office of Drug

Safety Policy and Communication should develop a cohesive risk
communication plan that includes, at a minimum, a review of all
center risk communication activities, evaluation and revision of
communication tools for clarity and consistency, and priority-
setting to ensure efficient use of resources. The work of the office
should be evaluated after one year.
The Advisory Committee Oversight and Management Staff in the Office of the Commis-
sioner works in collaboration with FDA centers to ensure consistent development, implementa-
tion, and operations of the FDA advisory committees (FDA, 2003).

BOX 6-5
Examples of Federal Advisory Committees
on Consumer Issues
Two DHHS agencies have successfully used consumer advisory
committees to obtain input from consumers. The NIH Director’s Council
of Public Representatives (COPR) advises the NIH director on “mat-
ters related to medical research, NIH policies and programs, and public
participation in agency activities.” The COPR has held workshops and
issued reports on enhancing public input in research priority-setting, on
strengthening public trust in the research enterprise, and on the orga-
nizational structure and management of NIH. The COPR Web site also
provides information about the cost of running the council: $222,351
for operations and member expenses and $124,118 for 1.30 full-time
equivalents of staff. NIH sponsors a public lecture series at which NIH
scientists discuss their work in a manner appropriate for a lay audience
(NIH, 2006); this series is another example of reaching out to understand
consumer concerns.
The National Cancer Institute (NCI) Office of Liaison Activities
launched the Director’s Consumer Liaison Group (DCLG) in 1997; it is
NCI’s first and only consumer advisory group. The DCLG makes recom-
mendations to the director of NCI from the consumer advocate perspec-
tive on a wide variety of issues, programs, and research priorities. The
15 members include advocates, survivors, family members, and health
care professionals and are chosen by the NCI director from a pool of ap-
plicants. The DCLG complies with the provisions of the Federal Advisory
Committee Act. (NCI, 2006a,b). It also provides a forum for the cancer
advocacy community. At the time of this writing, plans were being made
for a summit titled “Listening and Learning Together: Building a Bridge of
Trust” to bring together many segments of the cancer community to give
them a voice in shaping the interaction and collaboration between NCI
and consumers (NCI, 2006c). In 2003, NCI contracted with a consulting
firm to conduct a survey of the cancer advocacy community and, among
other things, to measure and track advocacy organizations’ perceptions of
the DCLG. The survey found that DCLG was known in the cancer advo-
cacy community, and 69% percent of respondents thought that the group
would be more effective if it worked strategically with NCI rather than
monitoring or participating in the implementation of NCI’s strategic plan.
Respondents also wanted to see the DCLG more involved in research,
clinical trials, survivorship, health disparities, and communication.

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Resources for the Drug Safety System
The Food and Drug Administration (FDA) lacks the resources needed to
accomplish its large and complex mission today, let alone to position itself
for an increasingly challenging future. Despite the fact that so much has
changed in drug discovery and development, in the number and complexity
of FDA’s congressionally mandated responsibilities, in the practice of medi-
cine, the structuring and delivery of health care, the way drugs are used,
the role of patients and consumers, and the information environment, FDA
appropriations for new drug review have remained roughly flat (in constant
dollars) since the passing of the Prescription Drug User Fee Act (PDUFA)
(Thompson, 2000; GAO, 2002). User fees have led to an overall increase
in resources for new drug review, but activities not funded by user fees
have received a smaller portion of FDA’s total budget. There is little dispute
that FDA in general is, and the Center for Drug Evaluation and Research
(CDER) specifically remains, severely underfunded (Goldhammer, 2005;
Wolfe, 2006). There is widespread agreement that resources for postmar-
keting drug safety work are especially inadequate and that resource limita-
tions have hobbled the agency’s ability to improve and expand this essential
Also of note: “Total FDA appropriations each year (exclusive of user fees and rent pay-
ments to GSA) must total at least as much as FDA received in FY 1997, adjusted for inflation
at the rate of change in the Consumer Price index since FY 1997. . . . FDA meets this trigger
consistently, even though for most years since FY 1997 FDA did not receive increases to cover
the cost of pay increases and inflation for its core programs—which was the original intent of
this trigger. FDA meets this trigger primarily because FDA has received appropriation increases
earmarked for specific initiatives since FY 1997 (e.g., food safety, tobacco, counter-terrorism)”
(FDA, 2003).
193

component of its mission. Continued resource shortages will impede the

agency’s ability to use new and future scientific and technological advances
in drug research across the lifecycle. In particular, the limited resources
could impede the agency’s ability to detect risks of new drugs in a timely
fashion, analyze emerging drug safety data, and effectively communicate
that information to the public in the ways envisioned in the committee’s
report. For fiscal year 2006, CDER’s enacted budget was $517,557,000,
with $297,716,000 from congressional appropriations and $219,841,000
(or 42.5 percent of the total budget) from user fees (see Figures 7-1 and 7-2
for more information on trends in CDER funding and staffing).
Although PDUFA has facilitated substantial expansion of CDER staff,
especially in the Office of New Drugs (OND), growth has been largely to
shorten review times and improve related processes, including interactions
with industry representatives and the development of guidances, rather than
strategic with respect to the full breadth of functions and disciplines needed
to operate the largest center of a world-class regulatory agency. PDUFA I
and II did not allow for the use of PDUFA funds to support postmarket-
ing drug safety work. PDUFA III allowed for a very restricted amount of
funds to be used for very specific and narrow postmarketing safety work
(postmarketing surveillance of drugs for 2–3 years after approval) (FDA,
$500.0
$450.0 Appropriations
User Fees
$400.0 Total Funding
$350.0
Amount (millions)
$300.0
$250.0
$200.0
$150.0
$100.0
$50.0
$0.0
1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004
Year
FIGURE 7-1 History of CDER funding.

SOURCE: PDUFA White Paper (FDA, 2005b).
fig 7-1

RESOURCES FOR THE DRUG SAFETY SYSTEM 195
3000
Total Process FTEs
User Fee FTEs
2500
Non-User Fee FTEs
2000
FTEs
1500
1000
500
0
1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004
Fiscal Year
FIGURE 7-2 History of CDER staffing.

SOURCE: PDUFA White Paper (FDA, 2005b).
fig 7-2
2003). These restrictions have contributed to a troubling resource imbalance
between OND and other CDER units (e.g., postmarketing safety activities,
compliance). Some effects or correlates of the resource imbalance between
OND and the Office of Drug Safety (ODS)/ Office of Surveillance and Epi-
demiology (OSE) are discussed in Chapter 3.
The committee recognizes that the recommendations in this report come
with a price tag, one that is most likely large and believes it would be ill-
advised to expect CDER to take on the many new responsibilities called for
in this report without new funds for strengthening the number and expertise
of staff, for intramural and extramural research, and for information tech-
nology. On the other hand, the committee believes that full implementation
of the recommendations it offers is essential. Although some of the recom-
mendations are more far-reaching than others, the committee believes each
of its recommendations will serve to improve the drug safety system.
For the past 15 years, user fees have supported a steadily increasing
share of CDER’s work. Many have argued that relying so heavily on indus-
try funds is inherently inappropriate and damaging to the reputation and
functioning of CDER, indeed, of any regulatory entity. Some CDER staff,
as well as some public advocates (Wolfe, 2006) have expressed discomfort
with this funding (DHHS and OIG, 2003; GAO, 2006; IOM Staff Notes,
5
2005–2006; Union of Concerned Scientists, 2006) based on real or perceived

“capture” of the agency, that is, that the center’s increasing dependence on
industry funding in itself creates a sense of obligation “to please” on the part
of the agency. The Pharmaceutical Research and Manufacturers of America
(PhRMA) itself has expressed a concern about this perception.
“We share a concern with FDA about the current balance between the user
fee portion and the appropriated portion of the review process,” PhRMA’s
Goldhammer says. As industry funding approaches half of the review budget,
“it has led to a perceptual issue that industry is paying for the review process
and that the American public, through its tax moneys, is not. We would hope
that can be dealt with in some way because we don’t want there to be the
perception that this is an industry-driven program” (Thompson, 2000).
The effects of user-fee funding are experienced differently by different

staff at CDER (IOM Staff Notes, 2005–2006). Some staff recognize no
impact on their day-to-day work of the source of their salary and support
the principle and practice of the user-fee system, while others expressed
concerns about the workload and time pressures that they feel have accom-
panied the PDUFA funding, cognizant that if industry were displeased with
CDER performance and worked to eliminate user fees (and appropriations
did not increase to close the shortfall), staff would have to be eliminated.
Yet other CDER staff, particularly CDER leadership and managers, describe
PDUFA as setting necessary performance goals that any responsible agency
should employ regardless of links to funding source, and deny that the goals
are used as anything more than targets. Indeed, the goals allow for review
times longer than the 6- and 10-month approval targets in up to 10 percent
of the cases for standard-rated and priority-rated new drug applications.
However, if CDER were to consistently miss the goals for time-to-approval,
the pharmaceutical industry would push for changes in PDUFA fees or other
arrangements in the following round of negotiations. This reality would
undoubtedly put pressure on CDER management to meet these targets.
For some staff and policy analysts, user-fee funding, combined with
industry’s considerable role in shaping PDUFA-associated goals and ex-
pectations, further reinforces the perception that the industry has become
a primary driver of the agency’s priorities and performance. The notion
As described in Chapter 2, some CDER new drug review staff assert that the workload
pressures to meet PDUFA goals are compounded by industry submissions that are not well
organized, submissions that come in on paper or with data that are not easily reanalyzed, or
on suboptimal management by their direct supervisors or team leaders. Some of these CDER
staff also reported that the biggest pressures come from 6-month priority approvals and not
from standard applications, the goal for which is 10 months for approval.
Zelenay has proposed eliminating the PDUFA sunset clause as a means to reduce the
industry’s bargaining power (Zelenay, 2005).

of “regulatory capture” has been employed to describe the state of affairs

created or, more likely, exacerbated by the user-fee system, namely, that
powerful industry interests control or strongly influence the regulatory
agency’s decision making.
Some have argued that eliminating industry funding for regulatory re-
view is in the best interest of the credibility of the drug safety system. Others
have argued that industry receives a valuable service (timely approval of
their products) and should be expected to pay for this, as long as agency
independence and the credibility of its scientific review remain intact. Oth-
ers argue that without extra funding from user-fee revenue, the delays in
new drug review observed prior to user fees will return since FDA budgets
will then be subject to fluctuations in the policitical climate and increased
pressures to reduce government spending. This too may compromise the
effectiveness of our drug approval system.
As described elsewhere in the report, PDUFA has included an exten-
sive number of performance goals (see Appendix C for a complete listing).
CDER reports yearly to Congress on how well it has met those goals (in
the performance goals letter submitted by the Secretary of the Department
of Health and Human Services (DHHS), see, for example, http://www.fda.
gov/cder/pdufa/default.htm). Along with performance goals, PDUFA in-
cludes restrictions on how CDER can use its funds. Each round of PDUFA
negotiations has led to more demands on CDER and continued restrictions
on CDER’s flexibility. The committee is not concerned about the existence
of performance goals in principle, but finds the limitations or “strings”
that direct how CDER can use PDUFA funds the most troubling aspect of
the arrangement.
7.1: To support improvements in drug safety and efficacy activi-

ties over a product’s lifecycle, the committee recommends that the
Administration should request and Congress should approve sub-
Adapted from the capture theory of regulation advanced by Stigler (1971) and critiqued by
Laffont and Tirole (1991) and by Carpenter and Ting (2004).
The industry has a powerful influence on the political process and on the regulatory envi-
ronment whether or not it funds the agency.

Similar arguments have been made regarding user-fee programs for other regulatory
agencies.
http://energycommerce.house.gov/107/hearings/03062002Hearing502/print.htm.
See Chapter 3 for a recommendation regarding institution of safety goals.
The committee is aware that other regulatory agencies, for example the Environmental
Protection Agency and the Federal Communications Commission, are supported in part by
specific user-fee programs. Some user fees go directly into the Treasury; other user fees go to
the agency and offset congressional appropriations. The committee has not done an exhaustive
analysis of other user-fee programs but is of the understanding that they are not associated with
significant requirements on how the agency uses the fees to achieve programmatic goals.

stantially increased resources in both funds and personnel for the

Food and Drug Administration.
The committee favors appropriations from general revenues, rather

than user fees, to support the full spectrum of new drug safety responsi-
bilities proposed in this report. This preference is based on the expectation
that CDER will continue to review and approve drugs in a timely manner
and that increasing attention to drug safety will not occur at the expense
of efficacy reviews but rather it will complement efficacy review for a life-
cycle approach to drugs. Congressional appropriations from general tax
revenues are a mechanism by which the public can directly, fairly, and ef-
fectively invest in the FDA’s postmarket drug safety activities. However, if
appropriations are not sufficient to fund these activities and user fees are
required, Congress should greatly reduce current restrictions on how CDER
uses PDUFA funds. Should the sources described above be insufficient,
alternatives that could be considered and evaluated by Congress include
but are likely not limited to a user fee associated with the consumption of
prescription medications and a sales tax on purchase of marketing services
by pharmaceutical companies.
By some estimates, more than a billion prescriptions are written each
year in the United States. A small tax on prescriptions could generate sig-
nificant funding to implement the recommendations made in this report. A
tax of ten cents on every prescription, for example, would generate more
than $100 million for the FDA budget. The administrative costs of collecting
such a tax would need to be considered as well as the ultimate incidence of
the tax. For example, collecting the tax from retailers or consumers at the
point of sale might have higher administrative costs than collecting it from
manufacturers. On the other hand, manufacturers might not know how
many prescriptions were filled out of a given amount of product sold to a
wholesales or retailer. An alternative approach might be to tax manufactur-
ers based on the value of sales (perhaps net of rebates). This would have
the advantage of more heavily taxing more expensive drugs, which would
tend to be the newest ones and the ones around which there is greatest un-
certainty about safety. Regardless of the taxation method used, it must be
considered that the ultimate incidence of the tax will be on consumers and
will be regressive. This tax would likely also have an effect on the costs of
and access to pharmaceuticals.
Another tax-based proposal would seek to accomplish two goals—
revenue enhancement and deterrence of excessive DTC advertising. A direct
tax on DTC advertising for newer drugs would have the advantage of link-
ing the decision to impose a tax with the finding that newer drugs necessar-
ily suffer from greater uncertainty with respect to safety and efficacy in the
general population, which is more heterogeneous than that studied in the

preapproval clinical trials. On the other hand, taxation of protected speech

can raise constitutional objections that have yet to be fully litigated before
the courts. An alternative is to deny the tax deductibility of pharmaceuti-
cal advertising. Just such a proposal was made in H.R. 1655: America Rx
Act, although in that case the resulting revenues were to be used to offer
discounts on prescription drugs to those in need.
Regardless of the source of the funds, the committee reiterates that the
functioning of a drug safety system that assesses a drug’s risks and benefits
throughout its lifecycle is too important a public health need to continue
to be underfunded.
The committee was charged with reviewing CDER’s resources but
concluded that it was not feasible to do a financial audit of CDER or a
detailed calculation of the costs for CDER or other stakeholders, including
the pharmaceutical industry, of implementing the recommendations in this
report. Convention dictates that federal agencies do not publicly articulate
resource needs that differ from those offered in the President’s budget, so
the committee was unable to understand fully what CDER and FDA leader-
ship estimate is needed to meet current objectives, let alone the expanded
responsibilities the committee envisions for the future. Thus, the commit-
tee can only offer general guidance and estimates of resources that will be
required to implement its recommendations; it does so with the caveat that
this list is most likely incomplete and is but a starting point for discussions
between FDA and congressional appropriations committees. CDER will
need carefully to assess their resource needs in light of the recommendations
in this report.
Staff: The first three 5-year cycles of PDUFA funding and accompanying
process improvements have led to dramatic shortening of the time required
for new drug approval, in great part due to the significant staff increases,
primarily in OND. The committee asserts that the next phase of improve-
ments, including staff increases, should focus on the postmarket activities
recommended in this report.
The committee notes certain facts about current staffing. CDER estimat-
ed that in 2004 it devoted 700 full-time equivalents (FTEs) for premarket
safety work and 393 FTEs (or 36 percent of total safety-related FTEs) for
postmarket safety work (FDA, 2005a,b). PDUFA funding supported 1320
FTEs for new drug review in 2004 and appropriations supported 1287 FTEs
(FDA, 2005a,b). CDER staff devoted to new drug review has approximately
doubled in the PDUFA era. Between 1996 and 2004, new drug review FTEs
supported by PDUFA increased by 125 percent (from 600 to 1320) whereas
ODS staff increased by 75 percent (from 52 to 90)10 (FDA, 2005a,b).
The committee recognizes that CDER will require a significant increase
10In 2004 eight of the ODS staff were funded by PDUFA.

in staff to meet the new responsibilities described in this report. CDER will
require new staff, for example, to participate more actively in efforts to gen-
erate more and better safety analyses, such as through an expanded epide-
miology contracts program; participate in new drug review teams; develop
more consistent approaches to risk-benefit assessment both premarket and
postmarket; evaluate risk minimization action plans; work with other fed-
eral agencies and departments in their efforts to improve their drug safety-
related activities; evaluate industry-submitted 5-year reviews; routinely
assess and make public emerging safety and effectiveness information, and
consider appropriate imposition of the newly clarified conditions on dis-
tribution. The committee’s recommendations will require additional staff
throughout CDER and with varied expertise, for example, epidemiology,
statistics, public health, medicine, pharmacy, informatics, programming,
law, regulatory policy, communication, as well as project management and
administration.
The committee recognizes that increases in postmarket safety staff must
be phased in over time. As CDER begins to implement the recommenda-
tions in this report and gradually increase their staff, the size of the needed
increase will become apparent to CDER and the Congress. Congress can
ensure this by requesting that CDER perform and make publicly available
a formal evaluation of staff needs, perhaps in the form of a work audit.
The FDA commissioner can serve an important role as a champion within
the government and in discussions with Congress for needed resources. The
committee also recognizes that other federal partners in drug safety will re-
quire additional staff to achieve a fully functioning postmarket drug safety
system, as described in Chapter 4.
Research funds: ODS/OSE is the CDER component most likely to have
primary responsibility for implementing the extramural and intramural
research activities called for in the report. The committee was concerned
by the very small and inadequate amount of funds for the epidemiology
contracts programs in particular. CDER will also require funds for extra-
mural contracts to improve their passive and active surveillance activities, in
addition to increased intramural use of drug utilization databases and other
datasets such as the General Practice Research Database.
The committee provides several estimates of needed funds for intramu-
ral and extramural research. The committee‘s lower bound estimate is that
an expanded epidemiology contracts program would cost $10 million.11 The
committee estimates that other agencies/departments also require similar
resources for epidemiology research contracts. The committee offers as a
11The current epidemiology contract program, funded at approximately $1 million, is
insufficient to complete one major study. The committee asserts that at least 10 drug safety
hypotheses could be explored through this or a similar program per year.

more ambitious estimate that the epidemiology contracts program at CDER

should be expanded to $60 million.12 This upper bound estimate does not
include the costs for research to be conducted by other DHHS agencies or
other departments, such as the Centers for Medicare and Medicaid Services
or the Department of Veterans Affairs.
The committee acknowledges that a financial investment will be re-
quired for the success of the public-private partnership (PPP) it recommends
for the prioritization and planning of confirmatory drug safety and efficacy
studies. The federal partners will require dedicated staff to make this part-
nership successful, in addition to research funds for studies. The committee
anticipates that pharmaceutical companies and other health care industries
will also fund some of this research.
The committee offers a lower bound estimate of $20 million per year
for start-up and administrative costs of the PPP. This is based on an estimate
for a research institute recently proposed to advance the Critical Path Initia-
tive.13 As Chapter 4 describes, the PPP will have responsibility for prioritiz-
ing and planning postmarket studies to address public health concerns, will
help advise on the design of such studies (including the postmarket study
commitments agreed upon by CDER and industry), and will facilitate nec-
essary collaborations between government agencies and departments, and
the pharmaceutical industry. Some studies conducted under the aegis of
the PPP will require new resources. Other studies will be ones likely done
absent the PPP. In these cases the PPP brings added value to the research
by advising on study design, but the conduct of the research itself will not
require incremental funds.
An upper bound estimate for the PPP should include the cost of a large
clinical trial. Although not all studies to be conducted under the aegis of
the PPP are large, complicated, and expensive, some necessary studies will
require significant new resources. The committee asserts that at least one
major drug safety question that is best answered with prospective research
of some magnitude could be addressed each year under the aegis of the PPP.
Some of these studies would be epidemiology studies using existing data,
such as those also conducted under the epidemiology contracts program.
Other studies would address narrowly defined safety concerns in specific
populations. As described in Chapter 4, some, if not most, of these studies
would not be incremental costs to the system, because they would have oc-
curred absent the PPP. However, it is not unreasonable to anticipate, and
12This is based on testimony to Congress in 2000 that an expanded epidemiology contracts
program would cost $50 million (Federal News Service, 2000). Using the Consumer Price
Index, this would cost $60 million in 2006.
13The Enhancing Drug Safety and Innovation Act of 2006 (S. 3807) authorizes appropria-
tions for the Reagan-Udall Institute.

it would be naïve to suggest otherwise, that on occasion significant new

resources will be required to fund a large, prospective, randomized clini-
cal trial to answer drug safety questions of pressing public health concern.
Thus, an upper bound estimate of the resources needed for the PPP on such
occasions is on the order of $150 million14 to be spread out over the period
of time the study is conducted.
Information technology (IT): The committee concluded from its conver-
sations with individual CDER staff that CDER’s IT systems are antiquated.
Upgrades of staff workstations are clearly part of CDER and FDA plans, but
there will be additional IT needs (e.g., servers, programmers, and training)
to implement several of the recommendations in Chapter 4 that should be
included in budget projections.
Other resource needs: The committee was tasked to assess only one as-
pect, drug safety, of CDER responsibilities. There are many important areas
of CDER work that the committee did not assess, for example compliance,
inspections, and the prevention of medication errors. The committee also
realizes that the already-initiated PDUFA IV negotiations will likely result in
additional requirements on CDER. The committee notes that both of these
factors could very well require additional funds for staff and research.
It is critical that CDER assess the center’s resource needs with particular
attention to ensuring that funding for premarketing product review and
postmarketing risk-benefit assessments is commensurate with:
1. The breadth of both sets of programs and activities, and

2. Their importance in achieving a lifecycle approach to drug safety
and efficacy that translates into how FDA regulates, studies, and
communicates about drugs with stakeholders in industry, health
care, academic research, and the public.
This process must be conducted with a keen awareness of the expec-

tations, needs, and perspectives of all stakeholders in the system and in a
transparent manner. It is incumbent on the leadership of the agency and the
center, as well as the Administration, to present to Congress a full review
and analysis of the levels of funding needed to fulfill the mission of the
center and the vision the committee has set forth. While resources might not
be immediately available, a public statement acknowledging the resource
needs is essential.
FDA’s centennial offers an occasion to celebrate the past and to give
serious consideration to what is needed to strengthen the agency’s central
14For example, the Clinical Antipsychotic Trials of Intervention Effectiveness cost $42.6 mil-
lion; the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attacks trial cost
$125 million; the Study of Tamoxifen and Raloxifene trial cost $118 million.

role in assuring the safety and efficacy of prescription drugs now and in
the future. Also, PDUFA reauthorization is just months away, and major
legislation addressing drug regulation has been prepared and considered.15
These circumstances make this a golden moment of opportunity to im-
prove fundamentally the way FDA regulation considers and responds to
the evolving understanding of risks and benefits of drugs, and the way all
stakeholders in the drug safety system perceive, study, and communicate
about those risks and benefits. As described in Chapter 1, there have been
many commissions and reports addressing issues similar to those contained
in this report. It is the committee’s fervent hope that Congress, FDA, and
the other stakeholders will seize the gathering momentum to invigorate the
drug safety system. The agency’s credibility and its ability to protect and
promote optimally the health of the American people cannot wait another
year or another decade.
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10, 2005].
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FDA’s Review Process for New Drug Applications: a Management Review. OEI-01-01-
00590. Washington, DC: OIG, FDA.
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http://www.fda.gov/oc/pdufa3/2003plan/default.htm [accessed October 10, 2005].
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voted to Drug Safety. Submitted to the Institute of Medicine Committee on the Assessment
of the US Drug Safety System by FDA.
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Ambulatory Care and Prevention Harvard Medical School Director of Research Harvard
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15The Enhancing Drug Safety and Innovation Act of 2006, http://help.senate.gov/S___.pdf.

Union of Concerned Scientists (UCS). 2006. FDA Scientists Pressured to Exclude, Alter
Findings; Scientists Fear Retaliation for Voicing Safety Concerns. [Online]. Available:
http://www.ucsusa.org/news/press_release/fda-scientists-pressured.html [accessed July
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tion always a better Food and Drug Administration? Food Drug Law J 60(2):261-338.

Appendix A
Moving Target: Changes at FDA During

the Course of the Study
DRUG SAFETY INITIATIVES

Many of the recent changes stem from the 2004 Food and Drug Ad-
ministration (FDA) Drug Safety Initiative. The purpose of the initiative is to
create a culture of openness and to enhance oversight in FDA. To achieve
that FDA has established the Drug Safety Oversight Board (DSB), proposed
a Drug Watch Web page, and is soliciting public input on how to expand
and establish communication channels with the public to increase transpar-
ency (FDA, 2005d).
DRUG SAFETY OVERSIGHT BOARD

The DSB was established in February 2005 (FDA, 2005d) to help FDA
realize its vision of culture of openness, enhanced oversight, and transpar-
ency in decision making. The DSB is charged with identifying, tracking, and
overseeing the management of important drug safety issues in the Center for
Drug Evaluation and Research (CDER) (CDER, 2005). A separate board
task is to facilitate timely external communication of drug safety issues.
Board members—all appointed by the FDA commissioner—include FDA
staff, medical experts in other Department of Health and Human Services
agencies, and other government departments, and medical experts and rep-
resentatives of patient and consumer groups. The DSB has 31 members. It
This section was compiled by Institute of Medicine staff with guidance from the Committee
on the Assessment of the US Drug Safety System.
205

met nine times from its inception through June 2006, and it has generally
discussed Patient Information Sheets, Public Health Advisories distributed
by CDER, and ways to strengthen CDER’s risk communication efforts.
DRUG WATCH
A Drug Watch Web page was proposed as part of FDA’s drug safety
initiative in February 2005 to improve communication with the public on
drug safety issues by putting information out as quickly as possible in an
easily accessible format. The goal of the proposed Drug Watch program is to
help patients and health care professionals make informed decisions on the
use of prescription drugs. Drug Watch will include emerging data and risk
information in a consumer-friendly form (information sheets) for healthcare
professionals and patients regarding drugs for which FDA is actively assess-
ing incoming safety information (FDA, 2005b,d).
A draft guidance on Drug Watch released in May 2005 (FDA, 2005f)
discussed how the inclusion of a drug on Drug Watch would not signify
that the drug is dangerous or should not be used; it only means that FDA is
investigating emerging safety signals. The information on each drug would
vary but could include “factual information about newly observed, serious
adverse events associated with the use of a drug that have been reported
to FDA”; “information about significant emerging risks that FDA believes
may be associated with a drug, but that might be avoided by appropriate
patient selection, monitoring, or use of concomitant therapy”; and notice
of an important risk minimization procedure that has been put into place
by the sponsor to alert healthcare providers and patients that there has been
a change in how a drug should be prescribed, dispensed, or used (FDA,
2005f). The DSB role in overseeing the Drug Watch program was described
above.
STRUCTURAL CHANGES AND LEADERSHIP CHANGES IN THE

CENTER FOR DRUG EVALUATION AND RESEARCH
In September 2004, CDER announced that it would be restructuring the
Office of New Drugs (OND) and has implemented this in phases throughout
2005–2006 (FDA and CDER, 2005). Phase I of the reorganization involved
the elimination of the Office of Drug Evaluation V (ODE V), which began
in May 2005 and is now complete. Phase II began in July 2005 with the
operation of the new Office of Oncology Drug Products. It also involved the
split of the Division of Neuropharmacological Drug Products in ODE I into
two new divisions: Neurology and Psychiatry. Phase III began in September
2005 with reassignment of staff in the Division of Therapeutic Biological
Internal Medicine Products and the Division of Review Management Policy

APPENDIX A 207
in ODE VI to other ODEs and divisions in OND, so that ODE VI could be

eliminated (FDA and CDER, 2005).
In October 2005, in his “State of CDER” address to center employees,
Steven Galson outlined a proposed center reorganization to “better align
staff functions with CDER’s goals and FDA’s public health mission” (FDA,
2005j). According to Dr. Galson, the three goals of the reorganization are to
position CDER to be able to participate fully in the Critical Path Initiative
(CPI), to increase visibility and a cross-center approach to drug safety, and
to centralize risk communication efforts (FDA, 2006a).
As of May 15, 2006, the changes that Dr. Galson outlined in 2005
were put into effect (FDA and CDER, 2005). The reorganization resulted
in the lifting of the status (to be at the same level as OND) of the Office
of Drug Safety (ODS) whose name was changed to Office of Surveillance
and Epidemiology (OSE) and which now reports to the office of the center
director. That was done in part to address the perception that drug safety
is solely the responsibility of ODS. A new office that reports to the center
director and serves as a catalyst for CPI activities was created, with clinical
pharmacology and the office of biostatistics reporting to that office. Another
change was elevating the Office of Policy and Communication to the office
of the center director.
LEADERSHIP CHANGES IN THE

FOOD AND DRUG ADMINISTRATION
Over the course of this study, several changes in leadership have taken
place in FDA. When the study began, Lester M. Crawford was the acting
commissioner; he was confirmed in July 2005 (FDA, 2005i). Soon after his
permanent appointment, Dr. Crawford made several changes in FDA lead-
ership, including appointing a new deputy commissioner for medical and
scientific affairs, deputy commissioner for operations and chief operating
officer, deputy commissioner for international and special programs, and
associate commissioner for legislation (FDA, 2005h).
In September 2005, Dr. Crawford abruptly resigned as FDA commis-
sioner (two months after confirmation). Shortly thereafter, President Bush
appointed Andrew C. von Eschenbach as the new acting commissioner, and
he is still serving in this capacity. In March 2006, President Bush nominated
Dr. von Eschenbach to be the permanent head of the agency; as of June
2006, confirmation hearings have not yet taken place.
In June 2005, FDA announced its search for a new director of drug
safety in CDER (FDA, 2005g). In late July 2005, the agency announced that
CDER Acting Director Steven Galson would be director. In September 2005,
FDA announced that it had selected Douglas Throckmorton as the deputy
director of CDER. In October 2005, Gerald Dal Pan was named director

of ODS. In April 2006, FDA announced the appointment of Paul Seligman

as the CDER associate director for safety policy and communication; this
was a newly created position to provide oversight of drug safety issues and
policies in CDER (FDA, 2006c).
During the study process, the committee referred to newly released
FDA and CDER guidance documents and reports. FDA made additional
important changes and undertook reviews of some of its programs. Those
are described below.
RECENT MATERIALS FROM THE

FOOD AND DRUG ADMINISTRATION
Guidance Documents
In March 2005, FDA released three final guidance documents to help
develop new ways to improve methods of assessing and monitoring risks
associated with drugs in clinical development:
• Guidance for Industry: Premarketing Risk Assessment (FDA et al.,

2005). This guidance focuses on what pharmaceutical companies
should consider throughout the clinical trial process to improve
the assessment and reporting of safety, to assess important safety
issues during trial registration and best practices for the use of data
from preapproval safety evaluations, and to build on FDA and
International Conference on Harmonisation guidances related to
preapproval safety assessments.
• Guidance for Industry: Development and Use of Risk Minimiza-
tion Action Plans (FDA, 2005a). This guidance outlines steps that
pharmaceutical companies can take to address goals and objectives
related to risk and suggests tools to minimize known risks posed by
drugs. These include the consistent use and definition of terms; a
framework for ensuring that benefits exceed risks; obtaining input
from the public, patients, and health care professionals when decid-
ing to initiate, revise, or end risk minimization plans; and making
certain that risk minimization efforts are successful by evaluating risk
minimization action plans.
• Guidance for Industry: Good Pharmacovigilance Practices and
Pharmacoepidemiologic Assessment (FDA, 2005e). This guidance
discusses how to increase postmarketing vigilance to identify safety
signals, investigation of the signals, interpreting the signals in terms
of risk, and using pharmacovigilance plans to speed the acquisition
of safety information with unusual safety signals.

APPENDIX A 209
Those guidance documents were issued as part of FDA’s effort to mini-

mize risks while preserving the benefits of medical products. FDA stated that
the guidance documents are part of the drug safety initiative announced in
2004 (FDA, 2005d) to improve drug safety and the commitment to trans-
parency (FDA News, 2005a).
FDA released a final guidance in January 2006 titled “Guidance for
Industry, Investigators, and Reviewers Exploratory IND Studies” (CDER,
2006). It was one FDA step to “advance the earliest phases of clinical re-
search in the development of innovative medical treatments” (FDA News,
2006a). The guidance discusses specific steps to be taken when exploratory
clinical studies on humans are done under an investigational new drug to
make the process more efficient and safe.
Reports
In November 2005, FDA announced the availability of a white paper
titled Prescription Drug User Fee Act (PDUFA): Adding Resources and
Improving Performance in FDA Review of New Drug Applications (FDA,
2005c). It was released shortly after FDA requested public input on PDUFA
provisions for FDA to consider during the renewal process for 2007 (FDA,
2005k). The white paper describes PDUFA goals, how they were imple-
mented or achieved by CDER, and the changes that have resulted from
PDUFA (that is, hiring of more medical reviewers, shorter approval times,
greater consistency, and increased workload) (FDA, 2005c).
In February 2006, a report commissioned by FDA, Evaluation of FDA’s
First Cycle Review Performance—Retrospective Analysis was released
(FDA News, 2006c). It showed a positive correlation between receiving ap-
proval on the first review cycle and pharmaceutical company consultation
with FDA before the beginning of the final phase of human testing (the end
of phase 2). The commissioner of FDA stated that “these meetings have
become one of the most valuable aspects of the drug development process”
(FDA News, 2006c). Deficiencies in safety assessment during the Investiga-
tional New Drug process were cited in the report as a main cause of multiple
review cycles, which potentially could have been avoided if a “milestone
meeting” had taken place where CDER staff could have made suggestions
for improving the quality of the initial applications (FDA News, 2006c).
Thereport was written by Booz Allen Hamilton in relation to the Prescription Drug User
Fee Amendments of 2002 (PDUFA III).

OTHER RELEVANT CHANGES AT

THE FOOD AND DRUG ADMINISTRATION AND
THE CENTER FOR DRUG EVALUATION AND RESEARCH
Labeling
On November 2, 2005, FDA started requiring that drug manufactur-
ers submit prescription drug label information to FDA in a new electronic
format. That was intended to allow patients and healthcare providers to
obtain information in FDA-approved package inserts (“labels”) with greater
ease (FDA News, 2006c). Drug manufacturers are now required to provide
FDA with accurate and up-to-date product and prescribing information in
a structured product labeling that can be electronically managed. These la-
bels will be the main source of information for a new interagency Web site,
“DailyMed,” a health information clearinghouse, which will provide up-
to-date information to consumers and healthcare providers free (National
Library of Medicine, 2006).
In January 2006, FDA announced a change in the prescription drug for-
mat for the package insert to provide clear and concise information so that
healthcare providers can make better use of the drug label to minimize risk
and medical errors in their patients (FDA News, 2006c). The final rule was
the first revision in 25 years and now requires that prescription information
for new and recently approved products meet new criteria. The change was
aimed at increasing the readability and accessibility of label information
and drawing health professionals and consumers’ attention to the most
important pieces of drug information before a product is prescribed. The
changes include the insertion of a “highlights” section that includes concise
information on the risks and benefits related to the drug, a table of contents
in the label, the date of initial approval of the drug, a toll-free number, and
Internet reporting information.
The labeling rule also established an important change in statutory in-
terpretation: preempting state product liability laws on the basis of FDA’s
approved label. The preamble to the labeling rule states that state laws
and judicial decisions that would have the effect of finding FDA-approved
labels inadequate or misleading are preempted by the federal rule (21 CFR
Parts 201, 314, and 601). That position has partial support in existing case
law, and FDA’s assertion of federal preemption under the new labeling rule
has not yet been tested in court (National Conference of State Legislatures,
2006).

APPENDIX A 211
PROGRAM REVIEWS OR EVALUATIONS
Advisory Committees
In May 2006, CDER announced that it was launching an internal
assessment of its Advisory Committee meeting system to establish best
practices surrounding that process. The assessment will be led by senior
management in CDER and will take a comprehensive look at current prac-
tices for nominating committee members, screening for conflicts of interest,
choosing expertise for specific meeting topics, and utilizing Special Govern-
ment Employees.
Postmarketing Study Commitments

In April 2006, FDA contracted with Booz Allen Hamilton for an
evaluation of FDA’s postmarket study process (phase IV commitments) for
collecting medical information (FDA Press Release, 2006). The evaluation
will comment on how FDA can increase consistency in requesting, facilitat-
ing, and reviewing postmarketing commitments among centers. Ultimately,
this will help FDA to request focused studies that result in the information
needed to assess safety postmarket.
Partnerships
In August 2005, FDA and the Association of American Medical Colleges
(AAMC) released the joint report Drug Development Science Obstacles and
Opportunities for Collaborations, which describes an array of opportuni-
ties for scientific breakthroughs to be undertaken through collaboration to
reach the goals of CPI (AAMC, 2006; AAMC et al., 2005; DeClaire, 2005).
The report states that those partnerships should focus on greater sharing
of knowledge, regulatory and legislative relief, earlier evaluation of drugs
in humans, and improved education and training for health professionals.
Some of the kinds of collaboration outlined in the report are to develop
mechanisms to learn from failed drug targets, establish joint models for
biomarker validation, set up a consortium to analyze and learn from failed
clinical trials, and develop agreements for sharing of information restricted
as intellectual property.
In November 2005, FDA, the European Commission, and the European
Medicines Agency extended by 5 years a confidentiality agreement that
began in September 2003 (FDA and EMEA, 2004; DeClaire, 2005; FDA
et al., 2005). The types of information covered by the agreement are legal
and regulatory issues, scientific advice, orphan drug designation, inspection
reports, marketing authorization procedures, and postmarketing surveil-

lance. The implementation of the confidentiality agreement was planned

to take place in several stages and is described in the implementation plan
finalized in September 2004 (FDA and EMEA, 2004).
FDA announced that the agency would partner with the Agency for
Healthcare Research and Quality (AHRQ) to launch an effort aimed at
increasing research collaboration and to foster communication between the
two agencies in December 2005 (FDA News, 2006b). FDA leaders stated
that the collaboration will increase their understanding of health outcomes
of prescription drugs, which will lead to better information to provide to the
public. One component of the collaboration was assignment of a member of
senior CDER leadership to a 12-month detail at AHRQ’s Center for Out-
comes and Evidence as senior adviser in pharmaceutical outcomes research
(FDA News, 2006b).
CRITICAL PATH INITIATIVE AND PARTNERSHIPS

In March 2004, FDA released the report entitled Innovation or Stag-
nation?—Challenge and Opportunity on the Critical Path to New Medical
Products (the Critical Path Initiative) (FDA, 2004). The report discussed
the lack of innovative technologies and science in recent years to help to
make drug development less expensive and more efficient. The goal of the
CPI is to make safe and effective treatments available to the public quicker
by using scientific innovations. The three dimensions outlined in the CPI
report are safety assessment, evaluation of medical utility, and product
industrialization.
FDA called for assistance from the public, academic researchers, fund-
ing agencies, and industry to help to reach that goal because it does not
believe that it can get there alone. A major objective of the CPI is to encour-
age new and increased collaborations among a broad array of experts to
develop innovative tools.
To reach its goal, FDA has partnered with the World Health Organiza-
tion, the Bill and Melinda Gates Foundation, biotechnology research firms,
AAMC, and others. After receiving feedback from those and other stake-
holders, FDA released the Critical Path Opportunities Report in March
2006 to identify the initiative’s six kinds of priority-targeted research. One
related to safety is the use of biomarkers to predict the performance of a
product during development and thus reduce uncertainties about safety or
effectiveness. If the biomarkers can be identified, validated, and shown to
improve health outcomes, FDA believes that these priorities “will increase
efficiency, predictability, and productivity of new medical products” (FDA,
2004, 2006b).
The main element related to drug safety in the CPI is improving tools
for assessing safety to detect drug safety issues as early as possible. Today,

APPENDIX A 213
safety issues are usually found during clinical trials or when drugs are on
the market. Tests for finding safety problems earlier are few and not reli-
able. The CPI highlights that there are great efforts to be made and that a
new safety toolkit would include the ability to predict failures due to safety
before human testing in clinical trials and to demonstrate safety before a
drug is on the market. The safety toolkit would lead to better safety stan-
dards by helping to predict safety performance efficiently and quickly and
will decrease uncertainty.
FDA announced its partnership with the Critical Path Institute (C-Path)
in December 2005 to help it to reach the goals of the CPI (FDA, 2006d).
C-Path is an independent, publicly funded, nonprofit organization founded
by FDA, the University of Arizona, and SRI International. It was created to
fulfill the mission of the CPI, which is to “create innovative collaborations
in education and research that enable the safe acceleration of the process
for developing new medical products” (The Critical Path Institute, 2006).
FDA leaders stated that some of the projects developed by C-Path will help
to achieve many of the objectives outlined in the opportunities list discussed
above.
In March 2006, shortly after the release of the Opportunities Report,
FDA announced that it will be taking on an advisory role in the new Predic-
tive Safety Testing Consortium of C-Path and five pharmaceutical compa-
nies. The partnership will “share internally developed laboratory methods to
predict the safety of new treatments before they are tested in humans” (FDA,
2006b). The collaboration is in line with the public-private partnerships
stressed as a major need to improve drug development in the CPI. CDER’s
J. Woodcock commented that this is a “concrete example of the power of
the collaborative nature of the Critical Path Initiative.”
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www.eurekalert.org/pub_releases/2005-10/ghcc-wds102805.php [accessed December

14, 2004].
FDA (Food and Drug Administration). 2004. Innovation Stagnation: Challenge and Opportu-
nity on the Critical Path to New Medical Products. [Online]. Available:http://www.fda.
gov/oc/initiatives/criticalpath/whitepaper.pdf [accessed October 10, 2005].
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Available: http://www.fda.gov/cder/guidance/6657qs&asext5-2.pdf [accessed May 6,
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FDA. 2005c. White Paper, Prescription Drug User Fee Act (PDUFA): Adding Resources and
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APPENDIX A 215
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Appendix B
Acronyms
ADR adverse drug report

AE adverse event
AER adverse event review
AERS Adverse Event Reporting System
AHRQ Agency for Healthcare Research and Quality
BLA biologics license application
CBER Center for Biologics Evaluation and Research

CDC Centers for Disease Control and Prevention
CDER Center for Drug Evaluation and Research
CDRH Center for Devices and Radiological Health
CERTS Center for Education and Research Therapeutics
CFR Code of Federal Regulations
CFSAN Center for Food Safety and Applied Nutrition
CGMPs Current Good Manufacturing Practices
CMS Centers for Medicare and Medicaid Services
COPR Council of Public Representatives
CVM Center for Veterinary Medicine
DDMAC Division of Drug Marketing, Advertising and

Communication
DDRE Division of Drug Risk Evaluation
DHHS Department of Health and Human Services
DSaRM Drug Safety and Risk Management Advisory Committee
217

DSB Drug Safety Oversight Board

DTCA direct-to-consumer advertising
ELA established license application

EMEA European Medicines Agency
EU European Union
FAA Federal Aviation Administration

FDA Food and Drug Administration
FDAMA Food and Drug Administration Modernization Act of 1997
FD&C Act Federal Food, Drug, and Cosmetic Act
FOIA Freedom of Information Act
FTC Federal Trade Commission
FTE full-time equivalent
FY fiscal year
GAO Government Accountability Office

GGP good guidance practice
GLP good laboratory practice
GMP good manufacturing practice
GPRD General Practice Research Database
GRMP good review manufacturing practice
HIPAA Health Insurance Portability and Accountability Act
IND Investigational New Drug

IOM Institute of Medicine
IRB institutional review board
IT information technology
MaPP Manual of Policies and Procedures

MHRA Medicines and Healthcare Products Regulatory Agency
NAS National Academy of Sciences

NASA National Aeronautics and Space Administration
NCTR National Center for Toxicological Research
NDA New Drug Application
NIH National Institutes of Health
NME new molecular entity
NSAID non-steroidal anti-inflammatory drug
ODE Office of Drug Evaluation

ODS Office of Drug Safety

APPENDIX B 219
OIG Office of Inspector General

OMB Office of Management and Budget
OMP Office of Medical Policy
OND Office of New Drugs
OP Office of Planning
OPaSS Office of Pharmacoepidemiology and Statistical Science
OSE Office of Surveillance and Epidemiology
PDUFA Prescription Drug User Fee Act

PLA product license application
RiskMAP risk minimization action plan
SRS Spontaneous Reporting System
UK United Kingdom
USDA US Department of Agriculture
VSD Vaccine Safety Datalink
WHO World Health Organization


Appendix C
PDUFA Performance Goals—All Years
The following list presents by fiscal year the performance measures set
forth in the letters referenced in Section 102(3) of the PDUFA. In those let-
ters, the timing of a number of the goals was conditional either (1) on the
date (July 2, 1993) upon which a supplemental appropriation was enacted
to permit FDA to collect PDUFA user fees, or (2) a specific performance
interval (e.g., 6 or 12 months after submission). Table C-1 lists the 29 goals
by fiscal year with appropriate goal measurement dates:
TABLE C-1 PDUFA Performance Goals, FY 1993–FY 1997

Timing of Measurement
Interim Goals by Fiscal Year Measurement Datea
Interim Goals of FY 93
1. Establish an industry/FDA working group upon Supplemental July 2, 1993
initiation of the user fee program. appropriation
date
2. Initiate a pilot computer-assisted PLA review End of FY 93 Sept. 30,
(CAPLAR) program during FY 93. 1993
Interim Goal of FY 94
1. Review and act upon 55 percent of complete NDA 12 months after Sept. 30,
and PLA/ELA submissions received during FY 94 end of FY 94 1995
within 12 months after submission date.
2. Review and act upon 55 percent of efficacy 12 months after Sept. 30,
supplementsb received during FY 94 within 12 months end of FY 94 1995
after submission date.
221

TABLE C-1 Continued

3. Review and act upon 55 percent of manufacturing 6 months after Mar. 31,
supplementsb received during FY 94 within 6 months end of FY 94 1995
applications received during FY 94 within 6 months end of FY 94 1995
after the resubmission date.
5. Implement performance tracking and monthly 6 months after July 2, 1994
monitoring of CBER performance within 6 months of 7/2/93
initial user fee payments.
6. Implement project management methodology for all 12 months after July 2, 1994
NDA reviews within 12 months of the initiation of 7/2/93
user fee payments.
and PLA/ELA submissions received during FY 95 end of FY 95 1996
supplements received during FY 95 within 12 months end of FY 95 1996
4. Review and act upon 70 percent of resubmitted 6 months after Mar. 31,
5. Recruit and bring on board 50 percent of FDA 3 months after Dec. 31,
incremental review staff by first quarter of FY 95. end of FY 94 1994
6. Implement project management methodology for 18 months after Jan. 2, 1995
all PLA/ELA reviews within 18 months of user fee 7/2/93
payments.
7. Eliminate overdue backlogs of efficacy and 18 months after Jan. 2, 1995
manufacturing supplements to NDAs within 18 7/2/93
months of initiation of user fee payments.
8. Eliminate overdue of NDAs within 24 months of 24 months after Jan. 2, 1995
initiation of user fees. 7/2/93
9. Eliminate overdue backlogs of PLAs, ELAs and PLA/ 24 months after Jan. 2, 1995
ELA supplements within 24 months of initiation of 7/2/93
user fees.
10. Adopt uniform computer-assisted NDA standards End of FY 95 Sept. 30,
during FY 95. 1995
and PLA/ELA submissions receive during FY 96 end of FY 96 1997

APPENDIX C 223
TABLE C-1 Continued

4. Review and act upon 80 percent of resubmitted 6 months after Mar. 31,
Five-Year Goals of FY 97
1. Review 90 percent of complete PLAs, ELAs, and 6 months after Mar. 31,
NDAs for priority applications within 6 months after end of FY 97 1998
submission date.
2. Review 90 percent of complete PLAs, ELAs, and 12 months after Sept. 30,
NDAs for standard applications within 12 months end of FY 97 1998
3. Review 90 percent of priority supplements to PLAs, 6 months after Mar. 31,
ELAs, and NDAs within 6 months after submission end of FY 97 1998
date.
4. Review 90 percent of standard supplements to PLAs, 12 months after Sept. 30,
ELAs, and NDAs that require review of clinical end of FY 97 1998
data (efficacy supplements) within 12 months after
submission.
5. Review 90 percent of supplements to PLAs, ELAs, 6 months after Mar. 31,
and NDAs that do not require review of clinical data end of FY 97 1998
(manufacturing supplements) within 6 months after
submission date.
6. Review 90 percent of complete applications 6 months after Mar. 31,
resubmitted following receipt of a non-approval letter end of FY 97 1998
within 6 months after the resubmission date.
7. Total review staff increment recruited and on board by End of FY 97 Sept. 30,
end of FY 97. 1997
aThe statute allows three additional months for review of original NDA, PLA, or ELA
submissions that involve major amendments within the last three months of their usual 6- or
12-month review intervals. In these cases, the measurement dates shown in this Appendix
move forward by 3 months.
bThe term “supplement” applies to both drug and biologic submissions. It includes
“amendments” to biologic submissions.

SOURCE: FDA (Food and Drug Administration). 1995. Appendix A: PDUFA Performance
Goals, FY 199–FY 1997. [Online]. Available: http://www.fda.gov/ope/pdufa/report95/appenda.

ENCLOSURE
PDUFA REAUTHORIZATION PERFORMANCE
GOALS AND PROCEDURES
The performance goals and procedures of the FDA Center for Drug Evalu-
ation and Research (CDER) and the Center for Biologics Evaluation and
Research (CBER), as agreed to under the reauthorization of the prescription
drug user fee program in the “Food and Drug Administration Moderniza-
tion Act of 1997,” are summarized as follows:
I. FIVE-YEAR REVIEW PERFORMANCE GOALS
Fiscal year 1998

1. Review and act on 90 percent of standard original New Drug Applica-
tion (NDAs) and Product License Applications (PLAs)/Biologic License
Applications (BLAs) filed during fiscal year 1998 within 12 months of
receipt.
2. Review and act on 90 percent of priority original NDA and PLA/BLA
submissions filed during fiscal year 1998 within 6 months of receipt.
3. Review and act on 90 percent of standard efficacy supplements filed
during fiscal year 1992 within 12 months of receipt.
4. Review and act on 90 percent of priority efficacy supplements filed dur-
ing fiscal year 1998 within 6 months of receipt.
5. Review and act on 90 percent of manufacturing supplements filed dur-
6. Review and act on 90 percent of all resubmitted original applications
filed during fiscal year 1998 within 6 months of receipt, and review and
act on 30 percent of Class 1 resubmitted original applications within 2
months of receipt.
Fiscal year 1999

1. Review and act on 90 percent of standard original NDA and PLA/BLA
submission filed during fiscal year 1999 within 12 months of receipt
and review and act on 30 percent within 10 months of receipt.
submission filed during fiscal year 1999 within 6 months of receipt.
during fiscal year 1999 within 12 months of receipt and review and act
on 30 percent with in 10 months of receipt.

APPENDIX C 225

ing fiscal year 1999 within 6 months of receipt and review and act on 30
percent of manufacturing supplements requiring prior approval within
4 months of receipt.
6. Review and act on 90 percent of Class 1 resubmitted original applica-
tions filed during fiscal year 1999 within 4 months of receipt and review
and act on 50 percent within 2 months of receipt.
tions filed during fiscal year 1999 within 6 months of receipt.
Fiscal year 2000

submissions filed during fiscal year 2000 within 12 months of receipt
during fiscal year 2000 within 12 months of receipts and review and
act on 50 percent within 10 months of receipt.
tions filed during fiscal year 2000 within 4 months and review and act
on 50 percent within 2 months of receipt.
Fiscal year 2001

submissions filed during fiscal year 2001 within 12 months and review
and act on 70 percent within 10 months of receipt.
during fiscal year 2001 within 12 months and review and act on 70
percent within 10 months of receipt.


ing fiscal year 2001 within 6 months of receipt and review and act on
70 percent within 2 months of receipt.
tions filed during the fiscal year 2001 within 4 months of receipt and
review and act on 70 percent within 2 months of receipt.
tions within 6 months of receipt.
Fiscal year 2002

during fiscal year 2002 within 10 months of receipt.
tions within 6 months of receipt.
These review goals are summarized in Tables C-2, C-3, and C-4:
TABLE C-2 Original NDAs/BLAs/PLAs and Efficacy Supplements

SUBMISSION COHORT STANDARD PRIORITY
FY 98 90% IN 12 MO 90% IN 6 MO
FY 99 30% IN 10 MO 90% IN 6 MO
90% IN 12 MO
FY 00 50% IN 10 MO 90% IN 6 MO
90% IN 12 MO
FY 01 70% IN 10 MO 90% IN 6 MO
90% IN 12 MO
FY 02 90% IN 10 MO 90% IN 6 MO

APPENDIX C 227
TABLE C-3 Manufacturing Supplements

MANUFACTURING SUPPLEMENTS MANUFACTURING
THAT DO NOT REQUIRE PRIOR SUPPLEMENTS THAT
SUBMISSION APPROVAL (“CHANGES BEING DO REQUIRE PRIOR
COHORT EFFECTED” OR “30-DAY SUPPLEMENTS APPROVAL
FY 98 90% IN 6 MO 90% IN 6 MO
FY 99 90% IN 6 MO 30% IN 4 MO
90% IN 6 MO
FY 00 90% IN 6 MO 50% IN 4 MO
90% IN 6 MO
FY 01 90% IN 6 MO 70% IN 4 MO
90% IN 6 MO
FY 02 90% IN 6 MO 90% IN 4 MO
TABLE C-4 Resubmission of Original NDAs/BLAs/PLAs

SUBMISSION COHORT CLASS 1 CLASS 2
FY 98 30% IN 2 MO 90% IN 6 MO
90% IN 6 MO
FY 99 50% IN 2 MO 90% IN 6 MO
90% IN 4 MO
FY 00 70% IN 2 MO 90% IN 6 MO
90% IN 4 MO
FY 01 90% IN 2 MO 90% IN 6 MO
FY 02 90% IN 2 MO 90% IN 6 MO
II. NEW MOLECULAR ENTITY (NME) PERFORMANCE GOALS

The performance goals for standard and priority original NMEs in each
submission cohort will be the same as for all of the original NDAs (including
NMEs) in each submission cohort but shall be reported separately.
For biological products, for purposes of this performance goal, all original
BLAs/PLAs will be considered to be NMEs.
III. MEETING MANAGEMENT GOALS
A. Responses to Meeting Requests:

1. Procedure: Within 14 calendar days of the Agency’s receipt of a
request from industry for a formal meeting (i.e., a scheduled face-to-

face, teleconference, or videoconference) CBER and CDER should

notify the requester in writing (letter or fax) of the date, time and
the place for the meeting, as well as expected Center participants.
2. Performance Goal: FDA will provide this notification within 14
days for 70 percent of requests (based on request receipt cohort
year) starting in FY99; 80 percent in FY00; and 90 percent in sub-
sequent fiscal years.
B. Scheduling Meetings:
1. Procedure: The meeting date should reflect the next available
date on which all applicable Center personnel are available to at-
tend, consistent with the component’s other business; however, the
meeting should be scheduled consistent with the type of meeting
requested. If the requested date for any of these types of meetings is
greater than 30, 60, or 75 calendar days (as appropriate) from the
date the request is received by the Agency, the meeting date should
be within 14 calendar days of the date requested.
Type A Meetings should occur within 30 calendar days of the
Agency receipt of the meeting request.
Type B Meetings should occur within 60 calendar days of the
Type C Meetings should occur within 75 calendar days of the
2. Performance Goal: 70 percent of meetings are held within the time-
frame (based on cohort year of request) starting in FY99; 80 percent
in FY00; and 90 percent in subsequent fiscal years.
C. Meeting Minutes:
1. Procedure: The Agency will prepare minutes which will be available
to the sponsor 30 calendar days after the meeting. The minutes will
clearly outline the important agreements, disagreements, issues for
further discussion, and action items from the meeting in bulleted
form and need not be in great detail.
2. Performance Goal: 70 percent of minutes are issued within 30
calendar days of date of meeting (based on cohort year of meeting)
starting in FY99; 80 percent in FY00; and 90 percent in subsequent
fiscal years.
D. Conditions:
For a meeting to qualify for these performance goals:

APPENDIX C 229
1. A written request (letter or fax) should be submitted to the review

division; and
2. The letter should provide:
a. A brief statement of the purpose of the meeting;
b. A listing of the specific objectives/outcomes the requester ex-
pects from the meeting;
c. A proposed agenda, including estimated times needed for each
agenda item;
d. A listing of planned external attendees;
e. A listing of requested participants/disciplines representative(s)
from the Center;
f. The appropriate time that supporting documentation (i.e., the
“backgrounder”) for the meeting will be sent to the Center (i.e.,
“x” weeks prior to the meeting, but should be received by the
Center at least 2 weeks in advance of the scheduled meeting for
Type A or C meetings and at least 1 month in advance of the
scheduled meeting for Type B meetings); and
3. The Agency concurs that the meeting will serve a useful purpose
(i.e., it is not premature or clearly unnecessary). However, requests
for a “Type B” meeting will be honored except in the most unusual
circumstances.
IV. CLINICAL HOLDS

A. Procedure: The Center should respond to a sponsor’s complete response
to a clinical hold within 30 days of the Agency’s receipt of the submis-
sion of such sponsor response.
B. Performance Goal: 75 percent of such responses are provided within 30
calendar days of the Agency’s receipt of the sponsor’s response starting
FY98 (cohort of date of receipt) and 90 percent in subsequent fiscal
years.
V. MAJOR DISPUTE RESOLUTION

A. Procedure: For procedural or scientific matters involving the review
of human drug applications and supplements (as defined in PDUFA)
that cannot be resolved at the divisional level (including a request for
reconsideration by the Division after reviewing any materials that are
planned to be forwarded with an appeal to the next level), the response
to appeals of decisions will occur within 30 calendar days of the Center’s
receipt of the written appeal.
B. Performance Goal: 70 percent of such answers are provided within 30

calendar days of the Center’s receipt of the written appeal starting in

FY99; 80 percent in FY00; and 90 percent in subsequent fiscal years.
C. Conditions:
1. Sponsors should first try to resolve the procedural or scientific issue
at the Divisional level. If it cannot be resolved at that level, it should
be appealed to the Office Director level (with a copy to the Division
Director) and then, if necessary, to the Deputy Center Director (with
a copy to the Office Director).
2. Responses should be either verbal (followed by a written confirma-
tion within 14 calendar days of the verbal notification) or written
and should ordinarily be to either deny or grant the appeal.
3. If the decision is to deny the appeal, the response should include
reasons for the denial and any actions the sponsor might take in
order to persuade the Agency to reverse its decision.
4. In some cases, further data or further input from others might be
needed to reach a decision on the appeal. In these cases, the “re-
sponse” should be the plan for obtaining that information (e.g.,
requesting further information from the sponsor, scheduling a meet-
ing with the sponsor, scheduling the issue for discussion at the next
scheduled available advisory committee).
5. In these cases, once the required information is received by the
Agency (including any advice from an advisory committee), the
person to whom the appeal was made, again has 30 calendar days
from the receipt of the required information in which to either deny
or grant the appeal.
6. Again, if the decision is to deny the appeal, the response should
include the reasons for the denial and any actions the sponsor might
take in order to persuade the Agency to reverse its decision.
7. N.B. If the Agency decides to present the issue to an advisory com-
mittee and there are not 30 days before the next scheduled advisory
committee, the issue will be presented at the following scheduled
committee meeting in order to allow conformance with advisory
committee administrative procedures.
VI. SPECIAL PROTOCOL QUESTION ASSESSMENT

AND AGREEMENT
A. Procedure: Upon specific request by a sponsor (including specific ques-
tions that the sponsor desires to be answered), the agency will evaluate
certain protocols and issues to assess whether the design is adequate to
meet scientific and regulatory requirements identified by the sponsor.

APPENDIX C 231
1. The sponsor should submit a limited number of specific questions

about the protocol design and the scientific and regulatory require-
ments for which the sponsor seeks agreement (e.g., is the dose range
in the carcinogenicity study adequate, considering the intended
clinical dosage; are the clinical endpoints adequate to support a
specific efficacy claim).
2. Within 45 days of Agency receipt of the protocol and specific ques-
tions, the Agency will provide a written response to the sponsor that
includes a succinct assessment of the protocol and answers to the
questions posed by the sponsor. If the agency does not agree that the
protocol design, execution plans, and data analyses are adequate to
achieve the goals of the sponsor, the reasons for the disagreement
will be explained in the response.
3. Protocols that qualify for this program include: carcinogenicity
protocols, stability protocols, and Phase 3 protocols for clinical
trials that will form the primary basis of an efficacy claim. (For
such Phase 3 protocols to qualify for this comprehensive protocol
assessment, the sponsor must have had an end of Phase 2/pre-Phase
3 meeting with the review division so that the division is aware of
the developmental context in which the protocol is being reviewed
and the questions being answered).
4. N.B. For products that will be using Subpart E or Subpart H devel-
opment schemes, the Phase 3 protocols mentioned in this paragraph
should be construed to mean those protocols for trials that will
form the primary basis of an efficacy claim no matter what phase
of drug development in which they happen to be conducted.
5. If a protocol is reviewed under the process outlined above and
agreement with the Agency is reached on design, execution, and
analyses and if the results of the trial conducted under the protocol
substantiate the hypothesis of the protocol, the Agency agrees that
the data from the protocol can be used as part of the primary basis
for approval of the product. The fundamental agreement here is
that having agreed to the design, execution, and analyses proposed
in protocols reviewed under this process, the Agency will not later
alter its perspective on the issues of design, execution or analyses
unless public health concerns unrecognized at the time of protocol
assessment under this process are evident.
B. Performance Goal: 60 percent of special protocols assessments
and agreement requests completed and returned to sponsor within
timeframes (based on cohort year of request) starting in FY99; 70
percent in FY00; 80 percent in FY01; and 90 percent in FY02.

VII. ELECTRONIC APPLICATIONS AND SUBMISSIONS

The Agency shall develop and update its information management infra-
structure to allow, by fiscal year 2002, the paperless receipt and processing
of INDs and human drug applications as defined in PDUFA, and related
submissions.
VIII. ADDITIONAL PROCEDURES

A. Simplification of Action Letters:
To simplify regulatory procedures, the CBER and the CDER intend to
amend their regulations and processes to provide for the issuance of either
an “approval” (AP) or a “complete response” (CR) action letter at the
completion of a review cycle for a marketing application.
B. Timing of Sponsor Notification of Deficiencies in Applications:
To help expedite the development of drug and biologic products, CBER and
CDER intend to submit deficiencies to sponsors in the form of an “informa-
tion request” (IR) letter when each discipline has finished its initial review
of its section of the pending application.
IX. DEFINITIONS AND EXPLANATION OF TERMS

A. The term “review and act on” is understood to mean the issuance of a
complete action letter after the complete review of a filed complete ap-
plication. The action letter, if it is not an approval, will set forth in detail
the specific deficiencies and, where appropriate, the actions necessary
to place the application in condition for approval.
B. A major amendment to an original application submitted within three
months of the goal date extends the goal date by three months.
C. A resubmitted original application is a complete response to an action
letter addressing all identified deficiencies.
D. Class 1 resubmitted applications are applications resubmitted after a
complete response letter (or a not approvable or approvable letter) that
include the following items only (or combination of these items):
1. Final printed labeling
2. Draft labeling
3. Safety updates submitted in the same format, including tabulations,
as the original safety submission with new data and changes high-
lighted (except when large amounts of new information including
important new adverse experiences not previously reported with
the product are presented in the resubmission)
4. Stability updates to support provisional or final dating periods

APPENDIX C 233
5. Commitments to perform Phase 4 studies, including proposals for

such studies
6. Assay validation data
7. Final release testing on the last 1–2 lots used to support approval
8. A minor reanalysis of data previously submitted to the application
(determined by the agency as fitting the Class 1 category)
9. Other minor clarifying information (determined by the Agency as
fitting the Class 1 category)
10. Other specific items may be added later as the Agency gains ex-
perience with the scheme and will be communicated via guidance
documents to industry.
E. Class 2 resubmissions that include any other items, including any item
that would require presentation to an advisory committee.
F. A Type A Meeting is a meeting which is necessary for an other-
wise stalled drug development program to proceed (a “critical path”
meeting).
G. A Type B Meeting is a 1) pre-IND, 2) end of Phase 1(for Subpart E or
Subpart H or similar products) or end of Phase 2/pre-Phase 3, or 3) a
pre-NDA/PLA/BLA meeting. Each requestor should usually only request
1 each of these Type B meetings for each potential application (NDA/
PLA/BLA) (or combination of closely related products, i.e., same active
ingredient but different dosage forms being developed concurrently).
H. A Type C Meeting is any other type of meeting.
I. The performance goals and procedures also apply to original applica-
tions and supplements for human drugs initially marketed on an over-
the-counter (OTC) basis through an NDA or switched from prescription
to OTC status through an NDA or supplement.
SOURCE: FDA. 2002. Enclosure: PDUFA Reauthorization Performance

Goals and Procedures. [Online]. Available: http://www.fda.gov/oc/pdu-
faIIIGoals.html [accessed June 21, 2006].

ENCLOSURE
PDUFA REAUTHORIZATION PERFORMANCE
GOALS AND PROCEDURES
The performance goals and procedures of the FDA Center for Drug Evalu-
ation and Research (CDER) and the Center for Biologics Evaluation and
Research (CDER), as agreed to under the reauthorization of the prescription
drug user fee program are summarized as follows:
I. REVIEW PERFORMANCE GOALS—FISCAL YEAR 2003

THROUGH 2007
A. NDA/BLA Submissions and Resubmissions:

Review and act on 90 percent of standard original NDA and BLA submis-
sions filed during fiscal year within 10 months of receipt.
1. Review and act on 90 percent of priority original NDA and BLA
submissions filed during fiscal year within 6 months of receipt.
2. Review and act on 90 percent of Class 1 resubmitted original ap-
plications filed during fiscal year within 2 months of receipt.
plications filed during fiscal year within 6 months of receipt.
Original Efficacy Supplements:

during fiscal year within 10 months of receipt.
2. Review and act on 90 percent of priority efficacy supplements filed
during fiscal year within 6 months of receipt.
Resubmitted Efficacy Supplements:

Fiscal Year 2003:
1. Review and act on 90 percent of Class 1 resubmitted efficacy
supplements filed during fiscal year 2003 within 6 months of receipt
2. Review and act on 90 percent of Class 2 resubmitted efficacy sup-
plements filed during fiscal year 2003 within 6 months of receipt.

APPENDIX C 235
Fiscal Year 2004:

plications filed during fiscal year 2004 within 6 months of receipt.
Fiscal Year 2005:
supplements within 6 months of receipt.
Fiscal Year 2006:
Fiscal Year 2007:
1. Review and act on 90 percent of Class 1 resubmitted efficacy sup-
plements filed during fiscal year 2007 within 2 months of receipt.
Original Manufacturing Supplements:
1. Review and act on 90 percent of manufacturing supplements filed
during fiscal year within 6 months of receipt and review and act on
90 percent of manufacturing supplements requiring prior approval
within 4 months of receipt.
These review goals are summarized in Tables C-5, C-6, C-7, and C-8:
TABLE C-5 Original and Resubmitted NDAs/BLAs
Original Applications 90% IN 10 MO 90% IN 6 MO
Class 1 Resubmissions 90% IN 2 MO 90% IN 2 MO
Class 2 Resubmissions 90% IN 6 MO 90% IN 6 MO
TABLE C-6 Original and Resubmitted Efficacy Supplements

Original Efficacy Supplements 90% IN 10 MO 90% IN 6 MO

TABLE C-7 Resubmitted Efficacy Supplements

SUBMISSION COHORT CLASS 1 CLASS 2
FY 2003 90% IN 6 MO 90% IN 6 MO
30% IN 2 MO
FY 2004 90% IN 4 MO 90% IN 6 MO
50% IN 2 MO
FY 2005 90% IN 4 MO 90% IN 6 MO
70% IN 2 MO
FY 2006 90% IN 4 MO 90% IN 6 MO
80% IN 2 MO
FY 2007 90% IN 2 MO 90% IN 6 MO
TABLE C-8 Manufacturing Supplements

MANUFACTURING
SUPPLEMENTS NO PRIOR
APPROVAL (“CHANGES BEING MANUFACTURING
SUBMISSION EFFECTED” OR “30-DAY SUPPLEMENTS THAT DO
COHORT SUPPLEMENTS”) REQUIRE PRIOR APPROVAL
FY 2003–2007 90% IN 6 MO 90% IN 4 MO
II. NEW MOLECULAR ENTITY (NME) PERFORMANCE GOALS

A. The performance goals for standard and priority original NMEs in
each submission cohort will be the same as for all of the original NDAs
(including NMEs) in each submission cohort but shall be reported
separately.
B. For biological products, for purposes of this performance goal, all
original BLAs will be considered to be NMEs.
III. MEETING MANAGEMENT GOALS

A. Responses to Meeting Requests
1. Procedure: Within 14 calendar days of the Agency’s receipt of a
request from industry for a formal meeting (i.e., a scheduled face-to-
face, teleconference, or videoconference) CBER and CDER should
notify the requester in writing (letter or fax) of the date, time, and
place for the meeting, as well as expected Center participants.
2. Performance Goal: FDA will provide notification within 14 days
for 90 percent in FY 2003–2007.

APPENDIX C 237
B. Scheduling Meetings
1. Procedure: The meeting date should reflect the next available
date on which all applicable Center personnel are available to at-
tend, consistent with the component’s other business; however, the
meeting should be scheduled consistent with the type of meeting
requested. If the requested date for any of these types of meetings is
greater than 30, 60, or 75 calendar days (as appropriate) from the
date the request is received by the Agency, the meeting date should
be within 14 calendar days of the date requested.
Type A Meetings should occur within 30 calendar days of the
Type B Meetings should occur within 60 calendar days of the
Type C Meetings should occur within 75 calendar days of the
2. Performance goal: 90 percent of meetings are held within the time-
frame (based on cohort year of request) from FY 03 to FY 07.
C. Meeting Minutes
1. Procedure: The Agency will prepare minutes which will be available
to the sponsor 30 calendar days after the meeting. The minutes will
clearly outline the important agreements, disagreements, issues for
further discussion, and action items from the meeting in bulleted
form and need not be in great detail.
2. Performance Goal: 90 percent of minutes are issued within 30 cal-
endar days of date of meeting (based on cohort year of meeting) in
FY03 to FY07.
D. Conditions
For a meeting to qualify for these performance goals:
1. A written request (letter or fax) should be submitted to the review
division; and
2. The letter should provide:
a. A brief statement of the purpose of the meeting;
b. A listing of the specific objectives/outcomes the requester ex-
pects from the meeting;
c. A proposed agenda, including estimated times needed for each
agenda item;
d. A listing of planned external attendees;

e. A listing of requested participants/disciplines representative(s)

from the Center;
f. The approximate time that supporting documentation (i.e., the
“backgrounder”) for the meeting will be sent to the Center (i.e.,
“x” weeks prior to the meeting, but should be received by the
Center at least 2 weeks in advance of the scheduled meeting
for Type A meetings and at least 1 month in advance of the
scheduled meeting for Type B and Type C meetings); and
g. The Agency concurs that the meeting will serve a useful pur-
pose (i.e., it is not premature or clearly unnecessary). However,
requests for a “Type B” meeting will be honored except in the
most unusual circumstances.
IV. CLINICAL HOLDS

B. Performance Goal: 90 percent of such responses are provided within 30
calendar days of the Agency’s receipt of the sponsor’s response in FY03
to FY07 (cohort of date of receipt).
V. MAJOR DISPUTE RESOLUTION

B. Performance Goal: 90 percent of such answers are provided within 30
calendar days of the Center’s receipt of the written appeal in FY03 to
FY07.
C. Conditions:
1. Sponsors should first try to resolve the procedural or scientific issue
at the Division level. If it cannot be resolved at that level, it should
be appealed to the Office Director level (with a copy to the Division
Director) and then, if necessary, to the Deputy Center Director.
2. Responses should be either verbal (followed by a written con-
firmation within 14 calendar days of the verbal notification) or
written.
3. If the decision is to deny the appeal, the response should include
reasons for the denial and any actions the sponsor might take.
4. In some cases, further data or further input from others might be
needed to reach a decision on the appeal. In these cases, the “re-
sponse” should be the plan for obtaining that information (e.g.,

APPENDIX C 239
requesting further information from the sponsor, scheduling a meet-

ing with the sponsor, scheduling the issue for discussion at the next
scheduled available advisory committee).
5. In these cases, once the required information is received by the
Agency (including any advice from an advisory committee), the
person to whom the appeal was made, again has 30 calendar days
from the receipt of the required information in which to either deny
or grant the appeal.
6. Again, if the decision is to deny the appeal, the response should
include the reasons for the denial and any actions the sponsor might
take in order to persuade the Agency to reverse its decision.
7. N.B. If the Agency decides to present the issue to an advisory com-
mittee and there are not 30 days before the next scheduled advisory
committee, the issue will be presented at the following scheduled
committee meeting in order to allow conformance with advisory
committee administrative procedures.
VI. SPECIAL PROTOCOL QUESTION ASSESSMENT

AND AGREEMENT
A. Procedure: Upon specific request by a sponsor (including specific ques-
tions that the sponsor desires to be answered), the agency will evaluate
certain protocols and issues to assess whether the design is adequate to
meet scientific and regulatory requirements identified by the sponsor.
1. The sponsor should submit a limited number of specific questions
about the protocol design and scientific and regulatory require-
ments for which the sponsor seeks agreement (e.g., is the dose range
in the carcinogenicity study adequate, considering the intended
clinical dosage; are the clinical endpoints adequate to support a
specific efficacy claim).
2. Within 45 days of Agency receipt of the protocol and specific ques-
tions, the Agency will provide a written response to the sponsor that
includes a succinct assessment of the protocol and answers to the
questions posed by the sponsor. If the agency does not agree that the
protocol design, execution plans, and data analyses are adequate to
achieve the goals of the sponsor, the reasons for the disagreement
will be explained in the response.
3. Protocols that qualify for this program include: carcinogenicity
protocols, stability protocols, and Phase 3 protocols for clinical
trials that will form the primary basis of an efficacy claim. (For
such Phase 3 protocols to qualify for this comprehensive protocol
assessment, the sponsor must have had an end of Phase 2/pre-Phase
3 meeting with the review division so that the division is aware of

the developmental context in which the protocol is being reviewed

and the questions being answered.)
4. N.B. For products that will be using Subpart E or Subpart H devel-
opment schemes, the Phase 3 protocols mentioned in this paragraph
should be construed to mean those protocols for trials that will
form the primary basis of an efficacy claim no matter what phase of
drug development in which they happen to be conducted.
5. If a protocol is reviewed under the process outlined above and
agreement with the Agency is reached on design, execution, and
analyses and if the results of the trial conducted under the protocol
substantiate the hypothesis of the protocol, the Agency agrees that
the data from the protocol can be used as part of the primary basis
for approval of the product. The fundamental agreement here is
that having agreed to the design, execution, and analyses proposed
in protocols reviewed under this process, the Agency will not later
alter its perspective on the issues of design, execution, or analyses
unless public health concerns unrecognized at the time of protocol
assessment under this process are evident.
B. Performance goal: 90 percent of special protocols assessments and
agreement requests completed and returned to sponsor within time-
frames (based on cohort year of request) from FY 03 to FY 07.
VII. CONTINOUS MARKETING APPLICATION

To test whether providing early review of selected applications and addi-
tional feedback and advice to sponsors during drug development for selected
products can further shorten drug development and review times, FDA
agrees to conduct the following two pilot programs:
A. Pilot 1—Discipline Review Letters for Pre-Submitted “Reviewable

Units” of NDAs/BLAs
1. This pilot applies to drugs and biologics that have been designated
to be Fast Track drugs or biologics, pursuant to section 112 of the
FDA Modernization Act (21 U.S.C. 506), have been the subject
of an End-of-Phase 2 and/or a Pre-NDA/BLA meeting, and have
demonstrated significant promise as a therapeutic advance in clini-
cal trials.
2. For drugs and biologics that meet these criteria, FDA may enter
into an agreement with the sponsor to accept pre-submission of
one or more “reviewable units”of the application in advance of the
submission of the complete NDA/BLA.

APPENDIX C 241
3. If following an initial review FDA finds a “reviewable unit” to

be substantially complete for review (i.e., after a “filing review”
similar to that performed on an NDA/BLA), FDA will initiate a
review clock for the complete review of the “reviewable unit” of the
NDA/BLA. The review clock would start from the date of receipt
of the “reviewable unit.”
4. To be considered fileable for review under paragraph 3, a “review-
able unit” must be substantially complete when submitted to FDA.
Once a “reviewable unit” is “filed” by FDA, except as provided in
paragraph 5 below, only minor information amendments submitted
in response to FDA inquiries or requests and routine stability and
safety updates will be considered during the review cycle.
5. Major amendments to the “reviewable unit” are strongly discour-
aged. However, in rare cases, and with prior agreement, FDA may
accept and consider for review a major amendment to a “review-
able unit.” To accommodate these rare cases, a major amendment
to a “reviewable unit” submitted within the last three months of a
6-month review cycle may, at FDA’s discretion, trigger a 3-month
extension of the review clock for the “reviewable unit” in question.
In no case, however, would a major amendment be accepted for
review and the review clock for the “reviewable unit” extended if
the extended review clock for the “reviewable unit” exceeded the re-
view clock for the complete NDA/BLA. (See paragraph 10 below.)
6. After completion of review of the “reviewable unit” of the NDA/
BLA by the appropriate discipline review team, FDA will provide
written feedback to the sponsor of the review findings in the form
of a discipline review letter (DRL).
7. The DRL will provide feedback on the individual “reviewable unit”
from the discipline review team, and not final, definitive decisions
relevant to the NDA/BLA.
8. If an application is to be presented to an advisory committee,
the final DRL on the “reviewable unit” may be deferred pending
completion of the advisory committee meeting and internal review
and consideration of the advice received.
9. The following performance goals will apply to review of “review-
able units” of an NDA/BLA for Fast Track drugs and biologics that
are submitted in advance of the complete NDA/BLA under this pilot
program: a. Discipline review team review of a “reviewable unit”
for a Fast Track drug or biologic will be completed and a DRL is-
sued within 6 months of the date of the submission for 30 percent
of “reviewable units” submitted in FY04; b. Discipline review team
review of a “reviewable unit” for a Fast Track drug or biologic will
be completed and a DRL issued within 6 months of the date of the

submission for 50 percent of “reviewable units” submitted in FY05;

c. Discipline review team review of a “reviewable unit” for a Fast
Track drug or biologic will be completed and a DRL issued within
6 months of the date of the submission for 70 percent “reviewable
units” submitted in FY06, and d. Discipline review team review
of a “reviewable unit” for a Fast Track drug or biologic will be
completed and a DRL letter issued within 6 months of the date of
the submission for 90 percent of “reviewable units” submitted in
FY07.
10. If the complete NDA/BLA is submitted to FDA while a 6-month re-
view clock for a “reviewable unit” is still open, FDA will adhere to
the timelines and performance goals for both the “reviewable unit”
and the complete NDA/BLA. For example, if a “reviewable unit”
is submitted in January and the complete NDA/BLA is submitted
in April, the review goal for the “reviewable unit” will be July and
the review goal for the complete NDA/BLA will be October.
11. Any resubmission or amendment of a “reviewable unit” submitted
by the sponsor in response to an FDA discipline review letter will
not be subject to the review timelines and performance goals pro-
posed above. FDA review of such resubmissions and amendments
in advance of submission of the complete NDA/BLA will occur only
as resources allow.
12. This pilot program is limited to the initial submission of an NDA/
BLA and is not applicable to a resubmission in response to an
FDA complete response letter following the complete review of an
NDA/BLA.
13. Guidance: FDA will develop and issue a joint CDER/CBER guid-
ance on how it intends to implement this pilot program by Septem-
ber 30, 2003. The guidance will describe the principles, processes,
and procedures that will be followed during the pilot program. The
guidance also will define what subsections of a complete technical
section would be considered an acceptable “reviewable unit” for
pre-submission and review and how many individual “reviewable
units” from one or more technical sections of an NDA/BLA can
be pre-submitted and reviewed subject to separate review clocks
under this program at any given time. The pilot program will be
implemented in FY 2004, after the final guidance is issued and will
continue through FY 2007.
B. Pilot 2—Frequent Scientific Feedback and Interactions During Drug

Development
1. This pilot applies to drugs and biologics that have been designated
to be Fast Track drugs or biologics pursuant to section 112 of the

APPENDIX C 243
FDA Modernization Act (21 U.S.C. 508), that are intended to treat
serious and/or life-threatening diseases, and that have been the sub-
ject of an end-of-phase 1 meeting. The pilot program is limited to
one Fast Track product in each CDER and CBER review division
over the course of the pilot program.
2. For drugs and biologics that meet these criteria, FDA may enter
into an agreement with the sponsor to initiate a formal program
of frequent scientific feedback and interactions regarding the drug
development program. The feedback and interactions may take
the form of regular meetings between the division and the spon-
sor at appropriate points during the development process, written
feedback from the division following review of the sponsor’s drug
development plan, written feedback from the division following
review of important new protocols, and written feedback from the
division following review of study summaries or complete study
reports submitted by the sponsor.
3. Decisions regarding what study reports would be reviewed as
summaries and what study reports would be reviewed as complete
study reports under this pilot program would be made in advance,
following discussions between the division and the sponsor of the
proposed drug development program. In making these decisions,
the review division will consider the importance of the study to
the drug development program, the nature of the study, and the
potential value of limited (i.e., based on summaries) versus more
thorough division review (i.e., based on complete study reports).
4. Guidance: FDA will develop and issue a joint CDER/CBER guidance
on how it intends to implement this pilot program by September
30, 2003. The guidance will describe the principles, processes, and
procedures that will be followed during the pilot program. The pilot
program will be implemented in FY 2004, after the final guidance
is issued and will continue through FY 2007. The full (unredacted)
study report will be provided to the FDA Commissioner and a ver-
sion of the study report redacted to remove confidential commercial
information or other information exempt from disclosure, will be
made available to the public.
C. Evaluation of the Pilot Programs

1. In FY 2004, FDA will contract with an outside expert consultant(s)
to evaluate both pilot programs.
2. The consultant(s) will develop an evaluation study design that
identifies key questions, data requirements, and a data collection
plan, and conduct a comprehensive study of the pilot programs to
help assess the value, costs, and impact of these programs to the

drug development and review process. A preliminary report will be

generated by the consultant by the end of FY06.
VIII. PRE- AND PERI-NDA/BLA

RISK MANAGEMENT PLAN ACTIVITIES
A. Submission and Review of pre-NDA/BLA meeting packages: A pre-
NDA/BLA meeting package may include a summary of relevant safety
information and industry questions/discussion points regarding pro-
posed risk management plans and discussion of the need for any post-
approval risk management studies. The elements of the proposal may
include:
1. assessment of clinical trial limitations and disease epidemiology
2. assessment of risk management tools to be used to address known
and potential risks
3. suggestions for phase 4 epidemiology studies, if such studies are
warranted
4. proposals for targeted post-approval surveillance (this would in-
clude attempts to quantify background rates of risks of concern
and thresholds for actions). The pre-NDA/BLA meeting package
will be reviewed and discussed by the review divisions as well as
the appropriate safety group in CDER or CBER.
B. Pre-NDA/BLA meeting with industry: This meeting may include a
discussion of the preliminary risk management plans and proposed
observational studies, if warranted, as outlined above. Participants in
this meeting will include product safety experts from the respective
Center. The intent of these discussions will be for FDA to get a bet-
ter understanding of the safety issues associated with the particular
drug/biologic and the proposed risk management plans, and to provide
industry with feedback on these proposals so that they can be included
in the NDA/BLA submission. It is the intent of this proposal that such
risk management plans and the discussions around them would focus
on specific issues of concern, either based on already identified safety
issues or reasonable potential focused issues of concern.
C. Review of NDA/BLA: The NDA/BLA submitted by industry may in-
clude the proposed risk management tools and plans, and protocols
for observational studies, based on the discussions that began with the
pre-NDA/BLA meeting, as described above, and may be amended as
appropriate to further refine the proposal. These amendments would
not normally be considered major amendments. Both the review divi-
sion and the appropriate safety group will be involved in the review of
the application and will try to communicate comments regarding the

APPENDIX C 245
risk management plan as early in the review process as practicable, in

the form of a discipline review letter. Items to be included in the risk
management plan to assure FDA of the safety and efficacy of the drug
or biologic are to be addressed prior to approval of an application. The
risk management plan may contain additional items that can be used
to help refine the risks and actions (e.g., background rates and obser-
vational studies) and these items may be further defined and completed
after approval in accordance with time frames agreed upon at the time
of product approval.
D. Peri-Approval Submission of Observational Study Reports and Peri-
odic Safety Update Reports (PSURs): For NDA/BLA applications, and
supplements containing clinical data, submitted on or after October 1,
2002, FDA may use user fees to review an applicant’s implementation of
the risk management plan for a period of up to two years post-approval
for most products and for a period of up to three years for products
that require risk management beyond standard labeling (e.g., a black
box or bolded warning, medication guide, restricted distribution). This
period is defined for purposes of the user fee goals as the peri-approval
period. Issues that arise during implementation of the risk management
plan (e.g., whether the plan is effective) will be reported to FDA either
in the form of a PSUR or in a periodic or annual report (21 CFR 314.80
and 314.81) (ICH Guidance E2C, Clinical Safety Data Management:
Periodic Safety Update Reports for Marketed Drugs) and addressed
during the peri-approval period through discussions between the ap-
plicant and FDA. PSURs may be submitted and reviewed semi-annually
for the first two or three years post approval to allow adequate time for
implementation of risk management plans. For drugs approved under
PDUFA III, FDA may use user fees to independently evaluate product
utilization for drugs with important safety concerns, using drug utiliza-
tion databases, for the first three years post approval. The purpose of
such utilization evaluations is to evaluate whether these products are
being used in a safe manner and to work pro-actively with companies
during the peri-approval period to accomplish this. FDA will allocate
$70,900,000 in user fees over 5 years to the activities covered in this
section. FDA will track the specific amounts of user fees spent on these
activities and will include in its annual report to Congress an accounting
of this spending.
E. Guidance Document Development: By the end of Fiscal Year 04,
CDER and CBER will jointly develop final guidance documents that
address good risk assessment, risk management, and pharmacovigilance
practices.

IX. INDEPENDENT CONSULTANTS FOR BIOTECHNOLOGY

CLINICAL TRIAL PROTOCOLS
A. Engagement of Expert Consultant: During the development period
for a biotechnology product, a sponsor may request that FDA en-
gage an independent expert consultant, selected by FDA, to partici-
pate in the Agency’s review of the protocol for the clinical studies
that are expected to serve as the primary basis for a claim.
B. Conditions
1. The product must be a biotechnology product (for example, DNA
plasmid products, synthetic peptides of fewer than 40 amino acids,
monoclonal antibodies for in vivo use, and recombinant DNA-
derived products) that represents a significant advance in the treat-
ment, diagnosis or prevention of a disease or condition, or have the
potential to address an unmet medical need;
2. The product may not have been the subject of a previously granted
request under this program;
3. The sponsor must submit a written request for the use of an in-
dependent consultant, describing the reasons why the consultant
should be engaged (e.g., as a result of preliminary discussions with
the Agency the sponsor expects substantial disagreement over the
proposed protocol); and
4. The request must be designated as a “Request for Appointment of
Expert Consultant” and submitted in conjunction with a formal
meeting request (for example, during the end-of-Phase II meeting
or a Type A, meeting).
C. Recommendations for Consultants: The sponsor may submit a list of
recommended consultants for consideration by the Agency. The selected
consultant will either be a special government employee, or will be
retained by FDA under contract. The consultant’s role will be advisory
to FDA and FDA will remain responsible for making scientific and
regulatory decisions regarding the clinical protocol in question.
D. Denial of Requests: FDA will grant the request unless the Agency de-
termines that engagement of an expert consultant would not serve a
useful purpose (for example it is clearly premature). FDA will engage
the services of an independent consultant, of FDA’s choosing, as soon
as practicable. If the Agency denies the request, it will provide a written
rationale to the requester within 14 days of receipt.
E. Performance Goal Change: Due to the time required to select and
screen the consultant for potential conflicts of interest and to allow the
consultant sufficient time to review the scientific issues involved, the
performance goals for scheduling the formal meeting (see section III)
may be extended for an additional sixty (60) days.

APPENDIX C 247
F. Evaluation: During FY 2006, FDA will conduct a study to evaluate the

costs and benefits of this program for both sponsors and the Agency.
X. FIRST CYCLE REVIEW PERFORMANCE PROPOSAL

A. Notification of Issues Identified During the Filing Review
1. Performance Goal: For original NDA/BLA applications and efficacy
supplements, FDA will report substantive deficiencies identified in
the initial filing review to the sponsor by letter, telephone confer-
ence, facsimile, secure e-mail, or other expedient means.
2. The timeline for such communication will be within 14 calendar
days after the 60 day filing date.
3. If no deficiencies were noted, FDA will so notify the sponsor.
4. FDA’s filing review represents a preliminary review of the applica-
tion and is not indicative of deficiencies that may be identified later
in the review cycle.
5. FDA will provide the sponsor a notification of deficiencies prior to
the goal date for 50 percent of applications in FY 2003, 70 percent
in FY 2004, and 90 percent in FY 2005, FY2006, and FY 2007.
B. Good Review Management Principles Guidance: FDA will develop a
joint CDER-CBER guidance on Good Review Management Principles
(GRMPs), and publish final guidance by the end of FY 2003. The Good
Review Management Principles will address, among other elements, the
following:
1. The filing review process, including communication of issues iden-
tified during the filing review that may affect approval of the
application.
2. Ongoing communication with the sponsor during the review pro-
cess (in accordance with 21 CFR 314.102(a)), including emphasis
on early communication of easily correctable deficiencies (21 CFR
314.102(b)).
3. Appropriate use of Information Request and Discipline Review let-
ters, as well as other informal methods of communication (phone,
fax, e-mail).
4. Anticipating/planning for a potential Advisory Committee
meeting.
5. Completing the primary reviews—allowing time for secondary and
tertiary reviews prior to the action goal date.
6. Labeling feedback—planning to provide labeling comments and
scheduling time for teleconferences with the sponsor in advance of
the action goal date.

C. Training: FDA will develop and implement a program for training all
review personnel, including current employees as well as future new
hires, on the good review management principles.
D. Evaluation: FDA will retain an independent expert consultant to under-
take a study to evaluate issues associated with the conduct of first cycle
reviews.
1. The study will be designed to assess current performance and
changes that occur after the guidance on GRMPs is published. The
study will include collection of various types of tracking data re-
garding actions that occur during the first cycle review, both from
an FDA and industry perspective (e.g., IR letters, DR letters, draft
labeling comments from FDA to the sponsor, sponsor response to
FDA requests for information).
2. The study will also include an assessment of the first cycle review
history of all NDAs for NMEs and all BLAs during PDUFA 3. This
assessment will include a more detailed evaluation of the events that
occurred during the review process with a focus on identifying best
practices by FDA and industry that facilitated the review process.
3. The study will also include an assessment of the effectiveness of the
training program implemented by FDA.
4. FDA will develop a statement of work for the study and will provide
the public an opportunity to review and comment on the statement
of work before the study is implemented. The consultant will pre-
pare annual reports of the findings of the study and a final study
report at the end of the 5-year study period. The full (un-redacted)
study reports will be provided to the FDA Commissioner and a
version of the study reports redacted to remove confidential com-
mercial information or other information exempt from disclosure,
will be made available to the public.
5. Development and implementation of the study of first cycle review
performance will be a component of the Performance Management
Plan conducted out of the Office of the Commissioner (see sec-
tion X).
6. Administrative oversight of the study will rest in the Office of the
Commissioner. The Office of the Commissioner will convene a
joint CDER/CBER review panel on a quarterly basis as a mecha-
nism for ongoing assessment of the application of Good Review
Management Principles to actions taken on original NDA/BLA
applications.
XI. IMPROVING FDA PERFORMANCE MANAGEMENT

A. Performance Fund: The Commissioner will use at least $7 million over

APPENDIX C 249
five years of PDUFA III funds for initiatives targeted to improve the drug
review process.
1. Funds would be made available by the Commissioner to the Cen-
ters based both on identified areas of greatest need for process
improvements as well as on achievement of previously identified
objectives.
2. Funds also could be used by the FDA Commissioner to diagnose
why objectives are not being met, or to examine areas of concern.
3. The studies conducted under this initiative would be intended to
foster:
a. Development of programs to improve access to internal and
external expertise
b. Reviewer development programs, particularly as they relate to
drug review processes,
c. Advancing science and use of information management tools
d. Improving both inter- and intra-Center consistency, efficiency,
and effectiveness
e. Improved reporting of management objectives
f. Increased accountability for use of user fee revenues
g. Focused investments on improvements in the process of drug
review
h. Improved communication between the FDA and industry
4. In deciding how to spend these funds, the Commissioner would
take into consideration how to achieve greater harmonization of
capabilities between CDER and CBER.
B. First Two Initiatives: Two specific initiatives will begin early in PDUFA
III and supported from performance management initiative funds 1)
evaluation of first cycle review performance, and 2) process review and
analysis within the two centers.
1. First Cycle Review Performance (See section X for details on this
proposed study.)
2. Process Review and Analysis
a. In FY 2003, FDA will contract with an outside consultant to
conduct a comprehensive process review and analysis within
CDER and CBER. This review will involve a thorough analysis
of information utilization, review management, and activity
cost.
b. The review is expected to take from 18–24 months, although
its duration will depend on the type and amount of complexity
of the issues uncovered during the review.
c. The outcome of this review will be a thorough documentation

of the process, a re-map of the process indicating where efficien-

cies can be gained, activity-based project accounting, optimal
use of review tools, and a suggested path for implementing the
recommendations.
d. FDA would anticipate delivery of a report of the consultant’s
findings and recommendations in FY 2004–2005. The agency
would consider these recommendations in planning any rede-
sign or process reengineering to enhance performance.
3. Further Studies
In subsequent years of PDUFA III, FDA may develop other study plans that
will focus on further analysis of program design, performance features and
costs, to identify potential avenues for further enhancement. Future studies
would be likely to include a comprehensive re-analysis of program costs
following the implementation of new PDUFA III review initiatives and the
adoption of any process changes following the recommendations of the year
1 and 2 studies.
XII. ELECTRONIC APPLICATIONS AND SUBMISSIONS—GOALS

A. The Agency will centralize the accountability and funding for all PDUFA
Information Technology initiatives/activities for CBER, CDER, ORA
and OC under the leadership of the FDA CIO. The July 2001 HHS IT 5-
year plan states that infrastructure consolidation across the department
should be achieved, including standardization. The Agency CIO will
be responsible for ensuring that all PDUFA III IT infrastructure and IT
investments support the Agency’s common IT goals, fit into a common
computing environment, and follow good IT management practices.
B. The Agency CIO will chair quarterly briefings on PDUFA IT issues to
periodically review and evaluate the progress of IT initiatives against
project milestones, discuss alternatives when projects are not progress-
ing, and review proposals for new initiatives. On an annual basis, an
assessment will be conducted of progress against PDUFA III IT goals
and, established program milestones, including appropriate changes to
plans. A documented summary of the assessment will be drafted and
forwarded to the Commissioner. A version of the study report redacted
to remove confidential commercial or security information, or other
information exempt from disclosure, will be made available to the
public. The project milestones, assessment and changes will be part of
the annual PDUFA III IT report.
C. FDA will implement a common solution in CBER, CDER, ORA and
OC for the secure exchange of content including secure e-mail, elec-
tronic signatures, and secure submission of, and access to application
components.

APPENDIX C 251
D. FDA will deliver a single point of entry for the receipt and processing
of all electronic submissions in a highly secure environment. This will
support CBER, CDER, OC and ORA. The system should automate the
current electronic submission processes such as checking the content of
electronic submissions for completeness and electronically acknowledg-
ing submissions.
E. FDA will provide a specification format for the electronic submission of
the Common Technical Document (e-CTD), and provide an electronic
review system for this new format that will be used by CBER, CDER
and ORA reviewers. Implementation should include training to ensure
successful deployment. This project will serve as the foundation for au-
tomation of other types of electronic submissions. The review software
will be made available to the public.
F. Within the first 12 months, FDA will conduct an objective analysis and
develop a plan for consolidation of PDUFA III IT infrastructure and
desktop management services activities that will assess and prioritize
the consolidation possibilities among CBER, CDER, ORA and OC to
achieve technical efficiencies, target potential savings and realize cost
efficiencies. Based upon the results of this analysis, to the extent appro-
priate, establish common IT infrastructure and architecture components
according to specific milestones and dates. A documented summary of
the analysis will be forwarded to the Commissioner. A version of the
study report redacted to remove confidential commercial or security
information, or other information exempt from disclosure, will be made
available to the public.
G. FDA will implement Capability Maturity Model (CMM) in CBER,
CDER, ORA and OC for PDUFA IT infrastructure and investments,
and include other industry best practices to ensure that PDUFA III IT
products and projects are of high quality and produced with optimal
efficiency and cost effectiveness. This includes development of project
plans and schedules, goals, estimates of required resources, issues and
risks/mitigation plans for each PDUFA III IT initiative.
H. Where common business needs exist, CBER, CDER, ORA and OC will
use the same software applications, such as eCTD software, and COTS
solutions.
I. Within six months of authorization, a PDUFA III IT 5-year plan will be
developed. Progress will be measured against the milestones described
in the plan.
XIII. ADDITIONAL PROCEDURES

A. Simplification of Action Letters
To simplify regulatory procedures, CBER and CDER intend to amend

their regulations and processes to provide for the issuance of either an

“approval” (AP) or a “complete response” (CR) action letter at the
completion of a review cycle for a marketing application.
B. Timing of Sponsor Notification of Deficiencies in Applications
To help expedite the development of drug and biologic products, CBER
and CDER intend to submit deficiencies to sponsors in the form of an
“information request” (IR) letter when each discipline has finished its
initial review of its section of the pending application.
XIV. DEFINITIONS AND EXPLANATION OF TERMS

A. The term “review and act on” is understood to mean the issuance of a
complete action letter after the complete review of a filed complete ap-
plication. The action letter, if it is not an approval, will set forth in detail
the specific deficiencies and, where appropriate, the actions necessary
to place the application in condition for approval.
B. A major amendment to an original application, efficacy supplement,
or resubmission of any of these applications, submitted within three
months of the goal date, extends the goal date by three months. A ma-
jor amendment to a manufacturing supplement submitted within two
months of the goal date extends the goal date by two months.
C. A resubmitted original application is a complete response to an action
letter addressing all identified deficiencies.
D. Class 1 resubmitted applications are applications resubmitted after a
complete response letter (or a not approvable or approvable letter) that
include the following items only (or combinations of these items):
1. Final printed labeling
2. Draft labeling
3. Safety updates submitted in the same format, including tabulations,
as the original safety submission with new data and changes high-
lighted (except when large amounts of new information including
important new adverse experiences not previously reported with
the product are presented in the resubmission)
4. Stability updates to support provisional or final dating periods
5. Commitments to perform Phase 4 studies, including proposals for
such studies
6. Assay validation data
7. Final release testing on the last 1–2 lots used to support approval
8. A minor reanalysis of data previously submitted to the application
(determined
9. Other minor clarifying information (determined by the Agency as
fitting the Class 1 category)

APPENDIX C 253
10. Other specific items may be added later as the Agency gains ex-
perience with the scheme and will be communicated via guidance
documents to industry.
E. Class 2 resubmissions are resubmissions that include any other items,
including any item that would require presentation to an advisory
committee.
F. A Type A Meeting is a meeting which is necessary for an other-
wise stalled drug development program to proceed (a “critical path”
meeting).
G. A Type B Meeting is a 1) pre-IND, 2) end of Phase 1 (for Subpart E
or Subpart H or similar products) or end of Phase 2/pre-Phase 3, or 3)
a pre-NDA/BLA meeting. Each requestor should usually only request
1 each of these Type B meetings for each potential application (NDA/
BLA) (or combination of closely related products, i.e., same active in-
gredient but different dosage forms being developed concurrently).
H. A Type C Meeting is any other type of meeting.
I. The performance goals and procedures also apply to original applica-
tions and supplements for human drugs initially marketed on an over-
the-counter (OTC) basis through an NDA or switched from prescription
to OTC status through an NDA or supplement.
SOURCE: FDA. 2005 (July 7). Enclosure: PDUFA Reauthorization Perfor-

mance Goals and Procedures. [Online]. Available: http://www.fda.gov/cder/
news/pdufagoals.htm [accessed July 3, 2006].


Appendix D
Committee on the Assessment of the US

Drug Safety System Meeting Agendas
MEETING ONE—AGENDA
The National Academies
Institute of Medicine
Meeting One
AGENDA
Wednesday, June 8, 2005

OPEN SESSION Room 100
10:00–10:05 a.m. Welcome and Introductions
David Blumenthal
Sheila Burke
Co-Chairs, Committee on the Assessment of the
US Drug Safety System
10:05–10:40 a.m. Charge to the Committee
Steven Galson
Acting Director of the Center for Drug Evaluation
and Research
Food and Drug Administration
255

Janet Woodcock
Deputy Commissioner of Operations
10:35–11:00 a.m. Questions from the Committee
11:00–11:45 a.m. Perspectives of Pharmaceutical Manufacturers and
Payors
Amit Sachdev
Executive Vice President, Health
Biotechnology Industry Organization (BIO)
Christine Simmon
Vice President of Public Affairs and Development
Generic Pharmaceutical Association (GPhA)
J. Russell Teagarden
Vice President of Clinical Practices &
Therapeutics
Medco Health Solutions, Inc. (on behalf of the
Pharmaceutical Care Management Association)
Alan Goldhammer
Associate Vice President for Regulatory Affairs
Pharmaceutical Research and Manufacturers of
America (PhRMA)
11:45–12:00 p.m. Questions from the Committee
12:00–12:45 p.m. Consumer/Patient and Professional Organizations’
Perspectives
David Borenstein
Member, Board of Directors
American College of Rheumatology (ACR)
John A. Gans
Executive Vice-President and Chief Executive
Officer
American Pharmacists Association (APhA)
Bill Vaughan
Senior Policy Analyst
Consumers Union
Jeanne Ireland
Director of Public Policy
Elizabeth Glaser Pediatric AIDS Foundation

APPENDIX D 257

1:00 p.m. Adjourn
MEETING TWO—AGENDA
Meeting Two
AGENDA
Speakers and Times Subject to Change
Tuesday, July 19, 2005
OPEN SESSION LECTURE ROOM
3:00–3:05 p.m. Welcome and Introductions
David Blumenthal
Sheila Burke
3:05–6:00 p.m. Public Comment
Carla Saxton
Professional Affairs Manager
American Society of Consultant Pharmacists
Maryann Napoli
Center for Medical Consumers
John J. Pippin
Physicians Committee for Responsible Medicine
Patrick J. Madden
Lesley Maloney
American Society of Health-System Pharmacists
Marc Wheat
Chief Counsel and Staff Director
Subcommittee on Criminal Justice, Drug Policy,
and Human Resources
US House of Representatives

Lindsey Johnson
Consumer Advocate
U.S. Public Interest Research Group (US PIRG)
Alison Rein
Assistant Director
Food & Health Policy National Consumers
League
Beth A. McConnell
Director
PennPIRG and the PennPIRG Education Fund
Marion J. Goff
Donald Klein
American College of Neuropsychopharmacology
Tom Woodward
Director, Alliance for Human Resource Protection
(AHRP)
State Director, International Coalition of Drug
Awareness
6:00 p.m. Adjourn
Wednesday, July 20, 2005

OPEN SESSION LECTURE ROOM
1:00–1:05 p.m. Welcome and Introductions
David Blumenthal
Sheila Burke
1:05–3:00 p.m. Food and Drug Administration’s (FDA’s) Drug Safety
Activities
Introduction and Overview
Paul J. Seligman
Director, Office of Pharmacoepidemiology and
Statistical Science
Center for Drug Evaluation and Research

APPENDIX D 259
Role of the Office of New Drugs in the Safety

Assessment
John K. Jenkins
Director of the Office of New Drugs
The Postmarketing Safety Assessment and the
Office of Drug Safety
Anne E. Trontell
Deputy Director, Office of Drug Safety
FDA Center for Drugs
Future of Safety Assessment
Paul J. Seligman
3:30–3:45 p.m. Break
3:45–4:00 p.m. The Role of the Agency for Healthcare Research and
Quality (AHRQ) in the US Drug Safety System
Scott R. Smith
Center for Outcomes and Evidence
Agency for Healthcare Research and Quality
4:00–4:15 p.m. The Role of the Centers for Medicare and Medicaid
Services (CMS) in the US Drug Safety System
Speaker TBA
Centers for Medicare and Medicaid Services
4:45–5:15 p.m. AHRQ-funded Centers for Education and Research
on Therapeutics (CERTs)
and
Contributions of Academia and the Pharmaceutical
Industry to Drug Safety Surveillance
Hugh Tilson
Chair, CERTs Steering Committee


5:45 p.m. Adjourn
WORKSHOP—AGENDA
Advancing the Methods and Application of
Risk-Benefit Assessment of Medicines
January 17, 2006
The Keck Center, Room 100
500 Fifth Street, NW
Washington, DC 20001
Purpose of workshop:
1. Identify methodological approaches for performing integrated and
explicit assessments of risk-benefit of pharmaceuticals throughout
a product’s lifecycle, including identifying the type of information
that would be most useful to decision-makers.
2. Obtain expert input on the use of new methodological approaches
in pre- and postmarket risk assessment.
3. Identify opportunities and barriers in advancing a public health ap-
proach to balancing risks and benefits of pharmaceuticals for drug
regulation and risk management.
Tuesday, January 17, 2005
8:15 a.m. Opening Remarks
8:30 a.m. Overview of Pharmacoepidemiology: What Is the
Evidence Base?
Session 1: Assessing a product’s risk-benefit balance throughout its lifecycle
involves the use of a variety of epidemiological resources and methods,
including the use of ad hoc data sources, automated data systems, and
randomized trials. The choice of specific assessment methods involves a con-
sideration of many factors, including how well it informs decision making
intended to optimize a drug’s balance between benefits and risks.

APPENDIX D 261
Assessing Risks and Benefits of Pharmaceuticals:

Methods and Approaches
Brian Strom, MD, MPH
Chair and Professor
Department of Biostatistics and Epidemiology
University of Pennsylvania
Premarket Assessment of Drug Safety at the FDA
Judith Racoosin, MD, MPH
Safety Team Leader
Division of Neurology Products
Division of Psychiatry Products
U.S. Food and Drug Administration
FDA Postapproval Risk Assessment
Anne Trontell, MD, MPH
Senior Advisor on Pharmaceutical Outcomes
Center for Outcomes and Evidence
Agency for Healthcare Policy and Research
Risk-Benefit Frameworks: Perspectives from the
Field of Environmental Health
Jonathan Samet, MD, MS
Professor and Chair
Department of Epidemiology
Johns Hopkins School of Public Health
9:45 a.m. Discussion: Q & A with IOM Committee Members
& Audience
10:30 a.m. Break
11:00 a.m. Case Studies Involving Risk-Benefit Uncertainties
Session 2: This session involves the consideration of two case studies of
contemporary drug safety issues, each case involving a different risk-benefit
dilemma. The case studies are intended to focus the discussion on the type
of information that would be most useful to decision makers, with the case
studies selected to address both the preapproval and the postapproval peri-
od. The intent is to model not what is or is not actually done at the FDA and
by the industry sponsors, but what could or should be done. The proposed
format is that speakers for each case study will briefly present the case study,
followed by questions of clarification of fact from the IOM Committee and
audience. Following lunch, there will be comments from an invited panel
and discussion/questions to be posed by the IOM Committee.

Presentation of Case Study 1—Salmeterol

Scott T. Weiss, MD
Professor of Medicine
Harvard Medical School
Presentation of Case Study 2—Muraglitazar
Steve Nissen, MD
Medical Director, Cardiovascular Coordinating
Center
Cleveland Clinic
Questions of Clarification of Fact
12:30 p.m. Lunch
1:30 p.m. Reconvene: Panel Discussions
Suggested Discussion Points for the Panelists: Having heard the case stud-
ies, what tool or tools (existing or to be developed) would have narrowed
the uncertainty about the benefit/risk profile for the drugs? At what point
during evidence development should this tool have been brought into play?
What would have remained uncertain? How long would it have taken and
what effort would it have taken to reduce that uncertainty? How were
the risks and benefits identified, evaluated, and weighted? Where were the
flaws in this process? What could have/should have been done differently
and why? What resources are needed for your approach? How would this
approach improve the current risk/benefit evaluation?
Panel:
Judith K. Jones, MD, PhD
President, The Degge Group, Ltd
Wayne Ray, PhD
Professor, Department of Preventive Medicine
Director, Pharmacoepidemiology
Vanderbilt University
Michael P. Stern, MD
Professor, Department of Medicine
Chief, Division of Clinical Epidemiology
University of Texas, San Antonio
Robert B. Wallace, MD, MS
Professor of Epidemiology, College of Public Health
University of Iowa

APPENDIX D 263
Noel Weiss, MD, PhD

Professor of Epidemiology, School of Public
Health and Community Medicine, University of
Washington
Discussion: Q & A with IOM Committee Members
and Audience
3:00 p.m. Break
3:30 p.m. Establishing a framework for risk-benefit methods to
reduce uncertainties during pharmacuetical products’s
lifecycle
Session 3: This session is designed to session to reflect on what we learned
from the case studies and panel discussion and to articulate a framework
needed to improve the timing, rigor, and transparency of risk-benefit
assessments.
Janice K. Bush, MD
VP, Quality, Education & Business Support, Benefit
Risk Management
Curt Furberg, MD, PhD
Professor, Wake Forest University
Louis Garrison, PhD
Professor of Pharmacy, University of Washington
Joanna Haas, MD, MS
Vice President, Pharmacovigilance, Genzyme
Corporation
Alastair J.J. Wood, MD
Professor, Vanderbilt University Medical Center
Discussion—All
5:00 p.m. Adjourn

MEETING FOUR—AGENDA
AGENDA
Thursday, January 19, 2006

OPEN SESSION
Keck 100
Welcome and Introductions
8:15–8:25 a.m.
Description of Committee’s request to invited
speakers
Many recommendations for strengthening FDA’s
role in drug safety have been made in the past
several years. We have sent today’s speakers three
sets of recommendations:
• Ganslaw LS. 2005. Drug Safety: New Legal/
Regulatory Approaches. FDLI Update: Food
and Drug Law, Regulation, and Education.
• FDA Task Force on Risk Management.
1999. Managing the Risks from Medical
Product Use: Creating a Risk Management
Framework. Report to the FDA Commis-
sioner from the Task Force on Risk Manage-
ment. http://www.fda.gov/oc/tfrm/riskman-
agement.pdf.
• CRS/Thaul. 2005. Drug Safety and Effec-
tiveness: Issues and Action Options After
FDA Approval. http://www.law.umaryland.
edu/marshall/crsreports/crsdocuments/
RL3279703082005.pdf.
Reflecting on these (and other recommenda-
tions you find relevant) please comment on the
following:
• Which of these or other recommendations
are the most important to consider and
why?
• Which of these or other recommendations
that have been made would you not support
and why?

APPENDIX D 265
8:25–8:45 a.m. Geoffrey Levitt

Wyeth Pharmaceuticals
8:45–9:05 a.m. Steven Ryder
Pfizer, Inc.
9:05–9:25 a.m. James Kotsanos
Eli Lilly and Company
9:25–9:45 a.m. James Nickas
Genentech
9:45–10:15 a.m. Questions from the Committee
10:15–10:30 a.m. Break
10:30–10:50 a.m. Fran Visco
National Breast Cancer Coalition
10:50–11:10 a.m. Sid Wolfe
Public Citizen
11:10–11:30 a.m. Frank Burroughs
Steve Walker
Abigail Alliance for Better Access to Developmental
Drugs
11:30–11:50 a.m. David H. Campen
Kaiser Permanente (on behalf of America’s Health
Insurance Plans)
11:50 a.m.– Questions from the Committee
12:20 p.m.
12:20–12:30 p.m. Closing Remarks
12:30 p.m. Adjourn


Appendix E
Summary
Preventing Medication Errors: Quality Chasm Series

267


Committee on Identifying and Preventing Medication Errors
Board on Health Care Services
Philip Aspden, Julie A. Wolcott, J. Lyle Bootman, Linda R. Cronenwett,

Editors
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Preventing medication errors / Committee on Identifying and Preventing Medication

Errors, Board on Health Care Services ; Philip Aspden ... [et al.], editors.
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ISBN-13: 978-0-309-10147-9 (hardcover)
ISBN-10: 0-309-10147-6 (hardcover)
1. Medication errors—Prevention. I. Aspden, Philip. II. Institute of Medicine (U.S.).
Committee on Identifying and Preventing Medication Errors. III. Series.
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www.national-academies.org

COMMITTEE ON IDENTIFYING AND PREVENTING

MEDICATION ERRORS
J. LYLE BOOTMAN (Co-chair), Dean and Professor, University of

Arizona College of Pharmacy; Founding and Executive Director,
University of Arizona Center for Health Outcomes and
PharmacoEconomic (HOPE) Research
LINDA R. CRONENWETT (Co-chair), Professor and Dean, School of
Nursing, University of North Carolina at Chapel Hill
DAVID W. BATES, Chief, Division of General Medicine, Brigham and
Women’s Hospital; Medical Director of Clinical and Quality Analysis,
Partners Healthcare System; Professor of Medicine, Harvard Medical
School
ROBERT M. CALIFF, Associate Vice Chancellor for Clinical Research,
Director of the Duke Clinical Research Institute, and Professor of
Medicine, Division of Cardiology, Duke University Medical Center
H. ERIC CANNON, Director of Pharmacy Services and Health and
Wellness, IHC Health Plans, Intermountain Health Care
REBECCA W. CHATER, Director of Clinical Services, Kerr Drugs, Inc./
KDI Clinical Services
MICHAEL R. COHEN, President, Institute for Safe Medication Practices
JAMES B. CONWAY, Senior Fellow, Institute for Healthcare
Improvement; Senior Consultant, Dana-Farber Cancer Institute;
Adjunct Lecturer on Health Care Management, Department of Health
Policy and Management, Harvard School of Public Health
R. SCOTT EVANS, Senior Medical Informaticist, Department of Medical
Informatics, LDS Hospital and Intermountain Health Care; Professor,
Department of Medical Informatics, and Adjunct Professor,
Department of Medicine, University of Utah
ELIZABETH A. FLYNN, Associate Research Professor, Department of
Pharmacy Care Systems, Harrison School of Pharmacy, Auburn
University
JERRY H. GURWITZ, Chief, Division of Geriatric Medicine and Dr. John
Meyers Professor of Primary Care Medicine, University of
Massachusetts Medical School; and Executive Director, Meyers
Primary Care Institute, University of Massachusetts Medical School,
Fallon Foundation, and Fallon Community Health Plan
CHARLES B. INLANDER, Former President, People’s Medical Society
KEVIN B. JOHNSON, Associate Professor and Vice Chair, Department of
Biomedical Informatics, and Associate Professor, Department of
Pediatrics, Vanderbilt University Medical School

WILSON D. PACE, Professor of Family Medicine and Green-Edelman

Chair for Practice-based Research, University of Colorado; Director,
American Academy of Family Physicians National Research Network
KATHLEEN R. STEVENS, Professor and Director, Academic Center for
Evidence-Based Practice, University of Texas Health Science Center,
San Antonio
EDWARD WESTRICK, Vice President of Medical Management,
University of Massachusetts Memorial Health Care
ALBERT W. WU, Professor of Health Policy and Management and
Internal Medicine, The Johns Hopkins University
Health Care Services Board

CLYDE J. BEHNEY, Acting Director (June 2005 to December 2005 and
from May 2006)
JOHN C. RING, Director (from December 2005 to May 2006)
JANET M. CORRIGAN, Director (September 2004 to May 2005)
ANTHONY BURTON, Administrative Assistant
Study Staff
PHILIP ASPDEN, Study Director
JULIE A. WOLCOTT, Program Officer (to April 2006)
ANDREA M. SCHULTZ, Research Associate (from June 2006)
RYAN L. PALUGOD, Research Assistant (from December 2005)
TASHARA BASTIEN, Senior Program Assistant (to January 2006)
WILLIAM B. MCLEOD, Senior Librarian
GARY J. WALKER, Senior Financial Officer (from December 2005)
TERESA REDD, Financial Advisor (to December 2005)
ELIZABETH E. LAFALCE, Intern (April to May, 2005)
vi

Reviewers
This report has been reviewed in draft form by individuals chosen for
their diverse perspectives and technical expertise, in accordance with proce-
dures approved by the NRC’s Report Review Committee. The purpose of
this independent review is to provide candid and critical comments that will
assist the institution in making its published report as sound as possible and
to ensure that the report meets institutional standards for objectivity, evi-
dence, and responsiveness to the study charge. The review comments and
draft manuscript remain confidential to protect the integrity of the delibera-
tive process. We wish to thank the following individuals for their review of
this report:
LOWELL ANDERSON, Watauga Corporation

MARGE BOWMAN, University of Pennsylvania Health System
PATRICIA FLATLEY BRENNAN, School of Nursing and College of
Engineering, University of Wisconsin-Madison
DAVID COUSINS, National Patient Safety Organization, London
DON E. DETMER, American Medical Informatics Association and
The University of Virginia
WILLIAM EVANS, St. Jude Children’s Research Hospital, Memphis
ANN HENDRICH, Ascension Health, St. Louis, MO
CRAIG HOESLEY, University Hospital, University of Alabama at
Birmingham
WILLIAM J. KOOPMAN, Department of Medicine, University of
Alabama at Birmingham
GERALD D. LAUBACH, Pfizer Inc., Past President
vii

viii REVIEWERS
LUCIAN LEAPE, Department of Health Policy and Management,

Harvard School of Public Health
ART LEVIN, Center for Medical Consumers, New York, NY
G. STEVE REBAGLIATI, Department of Emergency Medicine, Oregon
Health and Sciences University
HUGH TILSON, School of Public Health, University of North Carolina
Although the reviewers listed above have provided many constructive

comments and suggestions, they were not asked to endorse the conclusions
or recommendations nor did they see the final draft of the report before its
release. The review of this report was overseen by Paul F. Griner, University
of Rochester, Professor Emeritus and Charles E. Phelps, University of Roch-
ester. Appointed by the National Research Council and Institute of Medi-
cine, they were responsible for making certain that an independent exami-
nation of this report was carried out in accordance with institutional
procedures and that all review comments were carefully considered. Re-
sponsibility for the final content of this report rests entirely with the author-
ing committee and the institution.

Preface
In 2000, the Institute of Medicine (IOM) report To Err Is Human: Build-

ing a Safer Health System raised awareness about medical errors and accel-
erated existing efforts to prevent such errors. The present report makes clear
that with regard to medication errors, we still have a long way to go. The
current medication-use process, which encompasses prescribing, dispensing,
administering, and monitoring, is characterized by many serious problems
and issues that threaten both the safety and positive outcomes of the pro-
cess. Each of the steps in the process needs improvement and further study.
At the beginning of the medication-use process, prescribers often lack
sufficient knowledge about how the drugs they are prescribing will work in
specific patient populations. If the balance of medication risks and benefits
is not known (as is common, for example, with children and the elderly), it
is impossible to say whether medication use is safe. Improving medication
use and reducing errors, therefore, requires improving the quality of infor-
mation generated by the pharmaceutical industry and other researchers re-
garding drug products and their use in clinical practice. We also need to
better understand how to communicate such information to clinicians and
patients via packaging, leaflets, and health information technology systems.
Lastly, we need to understand how better to prevent medication errors in all
care settings and in transitions between care settings. In this report, the IOM
Committee on Identifying and Preventing Medication Errors proposes a re-
search agenda for industry and government that can help meet these critical
needs.
Despite the lack of data regarding many interventions that might im-
prove the quality and safety of medication use, the committee offers recom-
ix

x PREFACE
mendations for change that should be implemented and evaluated. People

who use medications to meet their health care needs have a huge stake in
that effort. The most powerful strategy for improving safety may be moti-
vating providers and organizations to support the full engagement of pa-
tients and surrogates in improving the safety of medication use. In addition,
providers and leaders of health care organizations must create the climate
and infrastructure necessary to continuously learn about and improve the
safety of all steps in the medication-use process. This report provides guid-
ance on the types of error prevention strategies that should be implemented
in each care setting. It also presents the committee’s recommendations for
the pharmaceutical industry, government, and regulatory, certification, and
accreditation bodies, each of which has a role to play in improving the qual-
ity and safety of medication use.
This report represents the culmination of the dedicated efforts of three
groups of people. We would like to thank our fellow committee members
who have worked long and diligently on this challenging study, the many
experts who provided formal testimony to the committee and informal ad-
vice throughout the study, and the staff of the Health Care Services Board
who managed the study and coordinated the writing of the final report.
J. Lyle Bootman, Ph.D., Sc.D.

Linda R. Cronenwett, Ph.D., M.A., R.N.
Cochairs
July 2006

Acknowledgments
The Committee on Identifying and Preventing Medication Errors wishes

to acknowledge the many people whose contributions and support made
this report possible. The committee benefited from presentations made by a
number of experts over the past 2 years. The following individuals shared
their research, experience, and perspectives with the committee: Tom
Abrams, Food and Drug Administration; Bruce Bagley, American Academy
of Family Physicians; Robert Ball, Food and Drug Administration; Jim
Battles, Agency for Healthcare Research and Quality; Karen Bell, Centers
for Medicare and Medicaid Services; Douglas Bierer, Consumer Healthcare
Products Association; David Bowen, Office of Senator Edward Kennedy;
Bill Braithwaite, eHealth Initiative; Dan Budnitz, Centers for Disease Con-
trol and Prevention; Betsy Chrischilles, University of Iowa; John Clarke,
ECRI; David Classen, First Consulting Group; Ilene Corina, Patients United
Limiting Substandards and Errors in Healthcare; Diane Cousins, U.S.
Pharmacopeial Convention; Loriann De Martini, California Department of
Health Services; Noel Eldridge, Veterans Health Administration; Frank
Federico, Institute for Healthcare Improvement; Susan Frampton, Planetree;
David Gustafson, University of Wisconsin; Ed Hammond, Duke University;
Mark Hayes, Office of Senator Chuck Grassley; Carol Holquist, Food and
Drug Administration; David Hunt, Centers for Medicare and Medicaid Ser-
vices; Gordon Hunt, Sutter Health; John Jenkins, Food and Drug Adminis-
tration; Mike Kafrissen, Johnson & Johnson; Ken Kizer, National Quality
Forum; Richard Moore, Massachusetts State Senator; Bill Munier, Agency
for Healthcare Research and Quality; Dianne Murphy, Food and Drug Ad-
ministration; Steve Northrop, Office of Senator Chuck Grassley; Jerry
xi

xii ACKNOWLEDGMENTS
Osheroff, Micromedex; Emily Patterson, Ohio State University; John

Reiling, Synergy Health and St. Joseph’s Hospital; Lisa Robin, Federation of
State Medical Boards; William Rollow, Centers for Medicare and Medicaid
Services; Jeffrey Rothschild, Brigham and Women’s Hospital Partners
Healthcare; Lee Rucker, American Association of Retired Persons; Luke
Sato, Harvard Risk Management Foundation; Stephen Schondelmeyer, Uni-
versity of Minnesota; David Schulke, American Health Quality Association;
Paul Schyve, Joint Commission on Accreditation of Healthcare Organiza-
tions; Paul Seligman, Food and Drug Administration; Vickie Sheets, Na-
tional Council of State Boards of Nursing; Pat Sodomka, Medical College of
Georgia; Scott Stanley, University Health System Consortium; Jonathan
Teich, Health Vision; Anne Trontell, Food and Drug Administration; Tim
Vanderveen, Alaris & Cardinal Health; and Ed Weisbart, Express Scripts.
The following individuals were important sources of information, gen-
erously giving their time and knowledge to further the committee’s efforts:
Michele Boisse, American Society for Clinical Pharmacology and Therapeu-
tics; Anne Burns, American Pharmacists Association; Francis Dobscha, Ad-
vance Med; Melody Eble, Johnson & Johnson; Atheer Kaddis, Blue Cross
and Blue Shield of Michigan; Lucinda Maine, American Association of Col-
leges of Pharmacy; Gary Merica, York Hospital; Joseph Morris, Health Care
Improvement Foundation; Richard Park, IVD Technology magazine; Ken
Reid, Washington Information Source Co.; Ed Staffa, National Association
of Chain Drug Stores; Kasey Thompson, American Society of Health-system
Pharmacists; Marissa Schlaifer, Academy of Managed Care Pharmacy;
Junelle Speller, American Academy of Pediatrics; Sharon Wilson, Center for
Nursing Practice; and Charles Young, Massachusetts Board of Registration
in Pharmacy.
The committee commissioned eight papers that provided important
background information for the report, and would like to thank all the
authors for their dedicated work and helpful insights: Harvey J. Murff,
Vanderbilt University; Ginette A. Pepper, University of Utah College of Nurs-
ing; Grace M. Kuo, Baylor College of Medicine; Marlene R. Miller, Karen
A. Robinson, Lisa H. Lubomski, Michael L. Rinke, and Peter J Pronovost,
The Johns Hopkins University; Benjamin C. Grasso, The Institute for Self-
Directed Care; Albert I. Wertheimer and Thomas M. Santella, Temple Uni-
versity; Eta Berner, University of Alabama at Birmingham with assistance
from Lorri Zipperer, Zipperer Project Management; Richard Maisiak, con-
sultant; and Brent Petty, The Johns Hopkins University.
The committee also benefited from the work of other committees and
staff of the Institute of Medicine that conducted studies relevant to this
report, particularly the Committee on Quality of Health Care in America
and the Committee on Identifying Priority Areas for Quality Improvement.
The Committee on Quality of Health Care in America produced the 2000

ACKNOWLEDGMENTS xiii
report To Err Is Human: Building a Safer Health System and the 2001 re-
port Crossing the Quality Chasm: A New Health System for the 21st Cen-
tury. The committee on Identifying Priority Areas for Quality Improvement
produced the 2003 report Priority Areas for National Action: Transforming
Health Care Quality.
Finally, funding for this project was provided by the Centers for Medi-
care and Medicaid Services. The committee extends special thanks for that
support.


Contents
SUMMARY 1
1 INTRODUCTION 25
PART I: UNDERSTANDING THE CAUSES AND COSTS OF
MEDICATION ERRORS 43
2 OVERVIEW OF THE DRUG DEVELOPMENT, REGULATION,
DISTRIBUTION, AND USE SYSTEM 50
3 MEDICATION ERRORS: INCIDENCE AND COST 105
PART II: MOVING TOWARD A PATIENT-CENTERED,
INTEGRATED MEDICATION-USE SYSTEM 143
4 ACTION AGENDA TO SUPPORT CONSUMER–PROVIDER
PARTNERSHIP 151
5 ACTION AGENDA FOR HEALTH CARE ORGANIZATIONS 221
6 ACTION AGENDA FOR THE PHARMACEUTICAL, MEDICAL
DEVICE, AND HEALTH INFORMATION TECHNOLOGY
INDUSTRIES 266
7 APPLIED RESEARCH AGENDA FOR SAFE MEDICATION
USE 310
8 ACTION AGENDAS FOR OVERSIGHT, REGULATION, AND
PAYMENT 328
xv

xvi CONTENTS
APPENDIXES
A BIOGRAPHICAL SKETCHES OF COMMITTEE MEMBERS 349
B GLOSSARY OF TERMS AND ACRONYMS 359
C MEDICATION ERRORS: INCIDENCE RATES 367
D MEDICATION ERRORS: PREVENTION STRATEGIES 409
INDEX 447

Summary
ABSTRACT
The use of medications is ubiquitous. In any given week, more
than four of five U.S. adults take at least one medication (prescrip-
tion or over-the-counter [OTC] drug, vitamin/mineral, or herbal
supplement), and almost a third take at least five different medica-
tions.1 Errors can occur with any of these products at any point in
the medication-use process and in any care setting. The frequency
of medication errors and preventable medication-related injuries
represents a very serious cause for concern.
The Centers for Medicare and Medicaid Services sponsored
this study by the Institute of Medicine (IOM) with the aim of
developing a national agenda for reducing medication errors based
on estimates of the incidence of such errors and evidence on the
efficacy of various prevention strategies. The study focused on the
safe, effective, and appropriate use of medications in the major
components of the medication-use system, addressing the use of
prescription drugs, OTC drugs, and complementary and alterna-
tive medications, in a wide range of care settings—hospital, long-
term, and community.
The committee estimates that on average, a hospital patient is
subject to at least one medication error per day, with considerable
1In this report, the terms medication and drug are used interchangeably.

2 PREVENTING MEDICATION ERRORS
variation in error rates across facilities. The few existing studies of

the costs associated with medication errors are limited to the health
care costs incurred by preventable injuries, and these are substantial.
At least a quarter of all medication-related injuries are prevent-
able. Many efficacious error prevention strategies are available,
especially for hospital care; examples are electronic prescribing and
clinical decision-support systems that check dosages and monitor
for harmful drug–drug interactions. This report provides guidance
on how to implement error prevention strategies in hospitals, long-
term care, and ambulatory care.
Establishing and maintaining a strong provider–patient part-
nership is a key approach for reducing medication errors. The
report outlines how such a partnership can be achieved and what
roles providers, patients, and third parties must play. For example,
consumers should maintain careful records of their medications,
providers should review a patient’s list of medications at each en-
counter and at times of transition between care settings (e.g., hospi-
tal to outpatient care), and the federal government should seek
ways to improve the quality of pharmacy leaflets and medication-
related information on the Internet for consumers.
Health care providers in all settings should seek to create high-
reliability organizations that constantly improve the safety and
quality of medication use. To this end, they should implement
active internal monitoring programs so that progress toward im-
proved medication safety can be accurately demonstrated. The re-
port offers guidance on appropriate monitoring systems for each
major care setting.
In carrying out this study, the IOM committee identified enor-
mous gaps in the knowledge base with regard to medication errors.
Current methods for generating and communicating information
about medications are inadequate and contribute to the incidence
of errors. Likewise, incidence rates of medication errors in many
care settings, the costs of such errors, and the efficacy of prevention
strategies are not well understood. The report proposes a research
agenda to address these and other knowledge gaps.
STUDY SCOPE
The Institute of Medicine (IOM) report To Err Is Human: Building a
Safer Health System (IOM, 2000) accelerated existing efforts to prevent
medication errors and improve the quality of health care, efforts that are just
now gaining acceptance as a discipline requiring investment in individuals
who specialize in error prevention and quality improvement. Against this
background, at the urging of the Senate Finance Committee, the United States

SUMMARY 3
BOX S-1
Scope of the Study
Congress, through the Medicare Modernization Act of 2003 (Section 107(c)),

mandated the Centers for Medicare and Medicaid Services to sponsor the Institute
of Medicine to carry out a study:
• To develop a fuller understanding of drug safety and quality issues through

the conduct of an evidence-based review of the literature, case studies and anal-
ysis. This review will consider the nature and causes of medication errors; their
impact on patients; and the differences in causation, impact and prevention across
multiple dimensions of health care delivery including patient populations, care set-
tings, clinicians, and institutional cultures.
• If possible, to develop estimates of the incidence, severity and costs of
medication errors that can be useful in prioritizing resources for national quality
improvement efforts and influencing national health care policy.
• To evaluate alternative approaches to reducing medication errors in terms
of their efficacy, cost-effectiveness, appropriateness in different settings and cir-
cumstances, feasibility, institutional barriers to implementation, associated risk,
and quality of evidence supporting the approach.
• To provide guidance to consumers, providers, payers, and other key stake-
holders on high-priority strategies to achieve both short-term and long-term drug
safety goals, to elucidate the goals and expected results of such initiatives and
support the business case for them, and to identify critical success factors and key
levers for achieving success.
• To assess opportunities and key impediments to broad nationwide imple-
mentation of medication error reductions, and to provide guidance to policy-
makers and government agencies in promoting a national agenda for medication
error reduction.
• To develop an applied research agenda to evaluate the health and cost
impacts of alternative interventions, and to assess collaborative public and private
strategies for implementing the research agenda through the Agency for Health-
care Research and Quality and other government agencies.
Congress directed the Centers for Medicare and Medicaid Services (CMS) to
contract with the IOM for a study to formulate a national agenda for reduc-
ing medication errors by developing estimates of the incidence of such errors
and determining the efficacy of prevention strategies (see Box S-1).
THE LEVEL AND CONSEQUENCES OF MEDICATION ERRORS

ARE UNACCEPTABLE
Rates of Errors and Preventable Harmful Events Are High

The frequency of medication errors and preventable adverse drug
events (ADEs) (defined in Box S-2) is a very serious cause for concern. In

BOX S-2
Key Definitions
Error: The failure of a planned action to be completed as intended (error of execu-

tion) or the use of a wrong plan to achieve an aim (error of planning). An error may
be an act of commission or an act of omission (IOM, 2004).
Medication error: Any error occurring in the medication-use process (Bates et al.,
1995a). Examples include wrong dosage prescribed, wrong dosage administered
for a prescribed medication, or failure to give (by the provider) or take (by the
patient) a medication.
Adverse drug event: Any injury due to medication (Bates et al., 1995b). Exam-
ples include a wrong dosage leading to injury (e.g., rash, confusion, or loss of
function) or an allergic reaction occurring in a patient not known to be allergic to a
given medication.
hospitals, errors are common during all steps of the medication-use

process—procuring the drug, prescribing, dispensing, administering, and
monitoring the patient’s response. In hospitals, they occur most frequently
at the prescribing and administration stages.
Published error rates depend on the intensity and specifics of the error
detection methods used. In particular, some methods are better suited to
certain stages of the medication-use process. Detection methods addressing
all stages but not including direct observation of administration found a
rate of 0.1 prescribing errors per patient per day in a study of hospital
pediatric units (Kaushal et al., 2001) and a rate of 0.3 prescribing errors per
patient per day in a study of hospital medical units (Bates et al., 1995a). A
major study using direct observation of administration (Barker et al., 2002)
carried out at 36 different health care facilities found an administration
error rate of 11 percent, excluding doses administered outside the sched-
uled time (“wrong-time” errors). Since a hospital patient receives on aver-
age at least ten medication doses per day, this figure suggests that on
average, a hospital patient is subject to one administration error per day.
Further, since prescribing and administration errors account for about three-
fourths of medication errors (Leape et al., 1995), the committee conserva-
tively estimates that on average, a hospital patient is subject to at least one
medication error per day. Substantial variations in error rates are found,
however. For the 36 facilities in the study mentioned above, the administra-
tion error rate (excluding wrong-time errors) ranged from 0 to 26 percent,
with a median value of 8.3 percent (Barker et al., 2002).
A preventable ADE is a serious type of medication error. ADEs, defined
as any injury due to medication (Bates et al., 1995b), are common in

SUMMARY 5
hospitals, nursing homes, and the outpatient setting. ADEs associated with
a medication error are considered preventable. The committee estimates
that at least 1.5 million preventable ADEs occur each year in the United
States:
• Hospital care—Classen and colleagues (1997) projected 380,000

preventable ADEs occurring annually, and Bates and colleagues (1995b)
450,000. These are likely underestimates given the higher preventable ADE
rate of another study using more comprehensive ADE identification meth-
ods (Jha et al., 1998).
• Long-term care—Gurwitz and colleagues (2005) projected 800,000
preventable ADEs, again likely an underestimate given the higher ADE
rates of other studies.
• Ambulatory care—Among outpatient Medicare patients alone,
Gurwitz and colleagues (2003) projected 530,000 preventable ADEs. Their
approach was conservative, however, because it did not involve direct con-
tact with patients, which yields much higher rates (Gandhi et al., 2003).
The above data exclude errors of omission—failure to prescribe medi-

cations for which there is an evidence base for the ability to reduce mor-
bidity and mortality. With respect to such errors, the committee found well-
documented evidence of inadequate treatments for acute coronary
syndromes, heart failure, chronic coronary disease, and atrial fibrillation,
as well as inadequate antibiotic and thrombosis prophylaxis in hospitals.
Morbidity Due to Medication Errors Is Costly

Current understanding of the costs of medication errors is highly incom-
plete. Most of what is known relates to additional health care costs associ-
ated with preventable ADEs, which represent the injuries caused by errors.
For hospital care, there is one estimate of the extra costs of inpatient
care for a preventable ADE incurred while in the hospital—$5,857 (Bates et
al., 1997). This figure excludes health care costs outside the hospital and
was derived from 1993 cost data. Assuming conservatively an annual inci-
dence of 400,000 in-hospital preventable ADEs, each incurring extra hospi-
tal costs of $5,857, yields an annual cost of $2.3 billion in 1993 dollars or
$3.5 billion in 2006 dollars.
For long-term care, as noted earlier, Gurwitz and colleagues (2005)
projected an annual incidence of 800,000 preventable ADEs. However,
there is no estimate of the associated health care costs for this group of
preventable ADEs.
For ambulatory care, the best estimate derives from a study (Field et al.,
2005) that calculateed the annual cost of preventable ADEs for all Medi-

care enrollees aged 65 and older. The cost in 2000 per preventable ADE
was estimated at $1,983, while national annual costs were estimated at
$887 million.
In addition to the likelihood of underestimation, the above estimates
are characterized by some important omissions. First, the costs of some
highly common medication errors, such as drug use without a medically
valid indication and failure to receive drugs that should have been pre-
scribed, were excluded from the Medicare study of ambulatory ADEs (Field
et al., 2005). Moreover, the costs of morbidity and mortality arising from
the failure of patients to comply with prescribed medication regimens were
not assessed. Second, all the studies omitted some important costs: lost
earnings, costs of not being able to carry out household duties (lost house-
hold production), and compensation for pain and suffering. Third, few data
are available for any setting regarding the costs of medication errors that do
not result in harm. While no injury is involved, these errors often create
extra work, and the costs involved may be substantial.
Effective Error Prevention Strategies Are Available

According to most studies, at least a quarter of all harmful ADEs are
preventable. Moreover, many efficacious error prevention strategies are
available, especially for hospital care. In the hospital setting, there is good
evidence for the effectiveness of computerized order entry with clinical
decision-support systems (Bates et al., 1998), for clinical decision-support
systems themselves (Evans et al., 1994), and for pharmacist participation
on hospital rounds (Leape et al., 1999). Bar coding and smart intravenous
(IV) pumps show promise for the hospital setting, but their efficacy has not
yet been clearly demonstrated.
Interventions consisting of educational visits appear to hold promise
for improving prescribing practices and patient outcomes in nursing homes.
Involving pharmacists in the management of medications in nursing homes
and ambulatory care also shows promise, but requires additional study.
This intervention has been most successful to date in populations with
certain conditions, such as diabetes.
IMPROVED PROVIDER–PATIENT COMMUNICATION IS VITAL

Achieving the patient-centered model of care envisioned in the IOM
report Crossing the Quality Chasm: A New Health System for the 21st
Century (IOM, 2001) will require a paradigm shift away from a paternalis-
tic, provider-centric model of care. Consumers (and their surrogates) should
be empowered as partners in their care, with appropriate communication,
information, and resources in place to support them. For medication safety,

SUMMARY 7
consumers and providers (including physicians, nurses, and pharmacists)

should know and act on patients’ rights, providers should engage in mean-
ingful communication about the safe and effective use of medications at
multiple points in the medication-use process, and government and other
participants should improve consumer-oriented written and electronic in-
formation resources.
Patient Rights
Patient rights are the foundation for the safe and ethical use of medica-
tions (see Box S-3). Ignoring these rights can have lethal consequences.
Millions of Americans take prescription drugs each year without being fully
informed by their providers about associated risks, contraindications, and
side effects. When clinically significant medication errors do occur, they
usually are not disclosed to patients or their surrogates unless injury or
death results.
Many but not all patient rights relating to medical care have been
established broadly in the U.S. Constitution (Amendments I and XIV) and
articulated by the courts through common law. Certain states have insti-
tuted a patient bill of rights relating to particular providers or care settings.
One important point not specifically addressed by these laws is the right for
a patient to be told when an adverse event occurs. Establishing a compre-
hensive set of patient rights in one document would facilitate patient and
BOX S-3
Patient Rights
Patients have the right to:
• Be the source of control for all medication management decisions that af-
fect them (that is, the right to self-determination).
• Accept or reject medication therapy on the basis of their personal values.
• Be adequately informed about their medication therapy and alternative
treatments.
• Ask questions to better understand their medication regimen.
• Receive consultation about their medication regimen in all health settings
and at all points along the medication-use process.
• Designate a surrogate to assist them with all aspects of their medication
management.
• Expect providers to tell them when a clinically significant error has occurred,
what the effects of the event on their health (short- and long-term) will be, and
what care they will receive to restore their health.
• Ask their provider to report an adverse event and give them information
about how they can report the event themselves.

provider understanding and exercise of these rights and improve the safety
and quality of medication use.
Actions for Consumers

For sound medication management, providers and consumers2 should
maintain an up-to-date record of medications being administered, including
prescription medications, over-the-counter (OTC) drugs, and dietary supple-
ments, as well as all known drug and/or food allergies. Such records are
especially important for patients who have chronic conditions, see multiple
providers, or take multiple medications.
By becoming more informed and engaged, consumers (and their surro-
gates) may decrease the probability of experiencing a medication error
(Cohen, 2000). Such actions can range from the simple and routine, such
as double-checking their prescription when dropping it off and picking it
up from the pharmacy, to the more involved, such as forming an active
partnership with providers in managing their health care. When using
OTC medications, herbal remedies, and dietary supplements, consumers
should seek the information they need to make informed decisions. When
obtaining medical care, consumers should ask questions and insist on
answers from providers to guide their decision making based on their
personal values and preferences. They should ensure that their provider
explains their medication regimen clearly and speak up if they do not
understand. In addition, they should ensure that providers give them writ-
ten information about their medications, as well as tell them where to
obtain information from other sources. Finally, consumers should commu-
nicate with their providers if they experience any unexpected changes in
the way they feel after initiating a new medication. Some specific actions
consumers can take are outlined in Box S-4.
Actions for Providers

Providers can take several specific actions to improve medication safety
(see Box S-5). First, they can verify the patient’s current medication list for
appropriateness at each encounter, and they can ensure that this list is
accurate at times of transition between care settings. They can educate
their patients about the medication regimen, understanding that patients
need different kinds of information at different times and for different
purposes. Providers can also respect patients’ wishes and inform them of
2In this report, the term consumers is often used in referring to patients to emphasize the
active role individuals need to take in ensuring the quality of the health care services they are
purchasing.

SUMMARY 9
BOX S-4
Consumer Actions to Enhance Medication Safety
Personal/Home
• Maintain a list of the prescription drugs, nonprescription drugs, and other

products, such as vitamins and minerals, you are taking.
• Take the list with you when you visit any medical practitioner, and have him
or her review it.
• Be aware of where to find educational material in your local community and
at reliable Internet sites.
Ambulatory Care/Outpatient Clinic
• Have the prescriber provide in writing the name of the drug (brand and
generic names, if available), what it is for, its dosage, and how often to take it, or
provide other written material with this information.
• Have the prescriber explain how to use the drug properly.
• Ask about the side effects of the drug and what to do if you experience a
side effect.
Pharmacy
• Make sure the name of the drug (brand or generic) and the directions
for use received at the pharmacy are the same as what is written down by the
prescriber.
• Know that you can review your list of medications with the pharmacist for
additional safety.
• Know that you have the right to counseling by the pharmacist if you have
any questions; you can ask the pharmacist to explain how to take the drug pro-
perly, what side effects it has, and what to do if you experience them (just as you
did with your prescriber).
• Ask for written literature about the drug.
Hospital Inpatient (Patient or Surrogate)
• Ask the doctor or nurse what drugs you are being given at the hospital.
• Do not take a drug without being told the reason for doing so.
• Exercise your right to have a surrogate present whenever you are receiving
medication and are unable to monitor the medication-use process yourself.
• Prior to surgery, ask whether there are medications, especially prescription
antibiotics, that you should take or any you should stop taking preoperatively.
• Prior to discharge, ask for a list of the medications you should be taking at
home, have a provider review them with you, and be sure you understand how the
medications should be taken.

BOX S-5
Issues for Discussion with Patients by Providers
(Physicians, Nurses, and Pharmacists)
• Review the patient’s medication list routinely and during care transitions.
• Review different treatment options.
• Review the name and purpose of the selected medication.
• Discuss when and how to take the medication.
• Discuss important and likely side effects and what to do about them.
• Discuss drug–drug, drug–food, and drug–disease interactions.
• Review the patient’s or surrogate’s role in achieving appropriate medication use.
• Review the role of medications in the overall context of the patient’s health.
their rights, including the right to have a surrogate present and involved
in their medication management whenever they are unable to monitor
their own medication use.
When communicating about medication errors that occur with the
potential for or actual harm, providers can tell patients how the error may
affect their health and what is being done to correct it. The vast majority of
patients want and expect to be told about errors, particularly those that
cause them harm.
Barriers Experienced by Consumers and Providers

In the current system, a number of barriers affect the ability of consum-
ers to engage in safe and effective use of medications and the ability of
providers to change their day-to-day practices to support new consumer-
oriented activities (Cohen, 2000). These barriers include (1) knowledge
deficits, such as patients lacking sufficient education about their medica-
tions and providers lacking the latest pharmacological knowledge about
particular drugs; (2) practical barriers, such as patients being unable to pay
for their medications and providers having to operate burdensome prescrib-
ing arrangements required by payers; and (3) attitudinal factors, such as
patients and providers having different cultural norms and beliefs about the
use of medications. These barriers often result in errors, such as taking the
wrong dose, taking a medication at the wrong time, or taking someone
else’s medication. Many of these barriers can be overcome by improved
consumer-oriented drug information, efforts on the part of providers to
respond to the challenges faced by their patients, and actions by health care
organizations to adopt a culture of safety and make more extensive use of
information technology.

SUMMARY 11
Recommendation 1: To improve the quality and safety of the

medication-use process, specific measures should be instituted
to strengthen patients’ capacities for sound medication self-
management. Specifically:
• Patients’ rights regarding safety and quality in health care and
medication use should be formalized at the state and/or federal
levels and ensured at every point of care.
• Patients (or their surrogates) should maintain an active list of
all prescription drugs, over-the-counter drugs, and dietary supple-
ments they are taking; the reasons for taking them; and any known
drug allergies. Every provider involved in the medication-use pro-
cess for a patient should have access to this list.
• Providers should take definitive action to educate patients (or
their surrogates) about the safe and effective use of medications.
They should provide information about side effects, contraindica-
tions, and how to handle adverse reactions, as well as where to
obtain additional objective, high-quality information.
• Consultation on their medications should be available to pa-
tients at key points in the medication-use process (during clinical
decision making in ambulatory and inpatient care, at hospital dis-
charge, and at the pharmacy).
Actions for Government and Other Stakeholders

Consumers should be able to obtain high-quality information about
medications not only from their providers, but also from the pharmacy and
Internet and community-based resources. However, these resources need
significant improvement in two overarching areas.
First, current materials (e.g., pharmacy information sheets [leaflets],
Internet-based information) are inadequately designed to facilitate consum-
ers’ ability to read, comprehend, and act on medication information. Phar-
macy leaflets are the source of such information most relied upon by con-
sumers. Yet a number of studies have revealed the inadequate quality of
these leaflets, as well as their variable quality from one pharmacy to an-
other and from one drug to another (Svarstad and Mount, 2001). Internet-
based health information has proliferated over the last decade, providing
consumers with immediate access to valuable resources such as medical
journals and libraries, but most consumers are unfamiliar with how to
access this information since it usually does not figure prominently during
online searches. Rather, consumers are directed to a multitude of other
sources of information with differing standards for the content provided.

The federal government should develop mechanisms for improving phar-

macy leaflets and the quality of Internet information for consumers.
Second, there is a need for additional resources beyond pharmacy leaf-
lets and Internet information that can be provided on a national scale. In
particular, a national drug information telephone helpline and community-
based health resource centers should be developed to promote consumer
education. Further, communication networks already in place, such as those
associated with the public health infrastructure (e.g., the Centers for Dis-
ease Control and Prevention’s National Center for Health Marketing) and
consumer networks should be used for broad dissemination of national
medication safety initiatives.
Recommendation 2: Government agencies (i.e., the Agency for

Healthcare Research and Quality [AHRQ], the Centers for Medi-
care and Medicaid Services [CMS], the Food and Drug Administra-
tion [FDA], and the National Library of Medicine [NLM]) should
enhance the resource base for consumer-oriented drug information
and medication self-management support. Such efforts require stan-
dardization of pharmacy medication information leaflets, improve-
ment of online medication resources, establishment of a national
drug information telephone helpline, the development of personal
health records, and the formulation of a national plan for the
dissemination of medication safety information.
• Pharmacy medication information leaflets should be standard-
ized to a format designed for readability, comprehensibility, and
usefulness to consumers. The leaflets should be made available to
consumers in a manner that accommodates their individual needs,
such as those associated with variations in literacy, language, age,
and visual acuity.
• The NLM should be designated as the chief agency respon-
sible for Internet health information resources for consumers. Drug
information should be provided through a consumers’ version of
the DailyMed program, with links to the NLM’s Medline Plus
program for general health and additional drug information.
• CMS, the FDA, and the NLM, working together, should un-
dertake a full evaluation of various methods for building and fund-
ing a national network of drug information helplines.
• CMS, the FDA, and the NLM should collaborate to confirm
a minimum dataset for personal health records and develop re-
quirements for vendor self-certification of compliance. Vendors
should take the initiative to improve the use and functionality of
personal health records by incorporating basic tools to support
consumers’ medication self-management.

SUMMARY 13
• A national plan should be developed for widespread distribu-

tion and promotion of medication safety information. Health care
provider, community-based, consumer, and government organiza-
tions should serve as the foundation for such efforts.
ELECTRONIC PRESCRIBING AND MONITORING FOR

ERRORS IN ALL CARE SETTINGS ARE ESSENTIAL
Safe medication use requires that clinicians synthesize several types of
information, including knowledge of the medication itself, as well as under-
standing of how it may interact with coexisting illnesses and medications
and how its use might be monitored. Several electronic supports can help
providers absorb and apply the necessary information.
Access to Automated Point-of-Care Reference Information

The underlying knowledge base is constantly changing, creating a situ-
ation in which it is almost impossible for health care providers to have
current knowledge of every medication they prescribe. Clinicians therefore
need access to critical syntheses of the evidence base. The Cochrane Col-
laboration (CC, 2005) is one such resource. In addition, many software
applications now being developed provide decision support for prescribing
clinicians (Epocrates, 2005). Applications of this type are typically avail-
able via the Internet or on personal digital assistants (PDAs). All prescribers
should use point-of-care reference information.
Electronic Prescribing
Paper-based prescribing is associated with high error rates (Kaushal et
al., 2003). Having all pharmacies receive prescriptions electronically would
result in fewer errors than occur with current paper or oral approaches
(Bates, 2001). Electronic prescribing is safer (Bates et al., 1998) because it
eliminates handwriting and ensures that the key fields (for example, drug
name, dose, route, and frequency) include meaningful data. More impor-
tant, as noted above, computerization enables the delivery of clinical deci-
sion support (Evans et al., 1998), including checks for allergies, drug–drug
interactions, overly high doses, and clinical conditions, as well as sugges-
tions for appropriate dosages given the patient’s level of renal function and
age. It should be noted that recent studies have identified implementation
problems and the unintended occurrence of new types of errors with these
computerized approaches (for example, pharmacy inventory displays of
available drug doses being mistaken for the usual or minimally effective
doses). Avoiding these problems requires addressing business and cultural

issues before such strategies are implemented and aggressively solving tech-
nological problems during the implementation process. Regulatory issues
must also be addressed for electronic transmission of prescriptions to be
practical.
Effective Use of Well-Designed Technologies

To deliver safe drug care, health care organizations should make effec-
tive use of well-designed technologies, which will vary by setting. Although
the evidence for this assertion is strongest in the inpatient setting (AHRQ,
2005), the use of technology will undoubtedly lead to major improvements
in all settings. In acute care, technologies should target prescribing by in-
cluding computerized provider order entry with clinical decision support.
Administration is also a particularly vulnerable stage in the medication-use
process, and several technologies are likely to be especially important in this
stage. These include electronic medication administration records, which
can improve documentation of what medications have been given and when,
as well as machine-readable identification, such as bar coding, and smart IV
infusion pumps. All these technologies should be linked electronically.
In nursing homes, computerized prescribing with decision support will
likely be important, although there has been little research on its efficacy
(Gurwitz et al., 2005). Moreover, implementation of computerized pre-
scribing in this setting will be challenging since most nursing homes have
very limited resources.
Some evidence suggests that computerized prescribing will be impor-
tant in the outpatient setting as well (Gandhi et al., 2003), although it may
not yield significant safety benefits without added decision support. Equally
important are likely to be approaches that improve communication be-
tween patients and providers.
Communication of Patient-Specific Medication-Related Information

The delivery of care often involves moving the locus of care among sites
and providers. These “handoffs” are fraught with errors. One strategy for
reducing errors during these care transitions is to reconcile medication
orders between transition points, especially between care settings such as
hospital and outpatient, but also between points within organizations, such
as the intensive care unit and a general care unit. This reconciliation in-
volves comparing what a patient is taking in one setting with what is being
provided in another to avoid errors of transcription and omission, duplica-
tion of therapy, and drug–drug and drug–disease interactions. This process
typically reveals many discrepancies (Pronovost et al., 2003).

SUMMARY 15
Reconciliation is facilitated when medication data are transmitted elec-

tronically among providers, with confirmation by the patient. Three impor-
tant steps are required. First, a complete and accurate medication list must
be compiled. Second, the data must be structured into components such as
the medication name, dose, route, frequency, duration, start date, and so
on. Third, these data must be formatted in a way that allows disparate
computer systems to understand both their structure and content.
The power of interoperable health care data was demonstrated after
the devastation of Hurricane Katrina. Pharmacy chains were able to make
patients’ medication lists available quickly to care providers, and states
with immunizations registries were able to retrieve immunization records,
enabling the enrollment of children in new schools.
Monitoring for Errors

All health care provider groups should seek to be high-reliability organi-
zations preoccupied with the possibility of failure (Reason, 2000). They
should implement active internal monitoring programs so that progress to-
ward improved medication safety can be accurately demonstrated. Voluntary
internal reporting systems have recognized limitations for evaluating the true
frequency of medication errors and ADEs (Flynn et al., 2002). Error detec-
tion methods that complement such systems should be used in all care set-
tings. These include computerized detection of ADEs, observation of medica-
tion passes in hospitals to assess administration errors, and audits of filled
prescriptions in community pharmacies to monitor dispensing errors.
Many external programs exist to which patients and providers can
report a medication error or hazardous situation (IOM, 2004). Voluntary
practitioner reporting to an external program will continue to be impor-
tant, as it is often the only way practitioners can effect change outside their
organizations. Errors need to be reported and analyzed if improvements in
care are to be achieved.
Adopting a Safety Culture

Patient safety can best be achieved through the adoption of a culture of
safety—an organizational commitment to continually seeking to improve
safety. To achieve a safety culture, senior management of health care orga-
nizations must devote sufficient attention to safety, as well as make suffi-
cient resources available for quality improvement and safety teams (IOM,
2004). Senior management must also authorize the investment of resources
in technologies that have been demonstrated to be effective but are not yet
widely implemented in most organizations, such as computerized provider
order entry systems and electronic health records. It has become increas-

ingly clear that the introduction of any of these technologies requires close
attention to business processes and ongoing maintenance. As noted above,
studies have shown that these tools can have unintended and adverse conse-
quences, and that avoiding these consequences requires addressing both
business and cultural issues.
Recommendation 3: All health care organizations should immedi-

ately make complete patient-information and decision-support
tools available to clinicians and patients. Health care systems should
capture information on medication safety and use this information
to improve the safety of their care delivery systems. Health care
organizations should implement the appropriate systems to enable
providers to:
• Have access to comprehensive reference information concern-
ing medications and related health data.
• Communicate patient-specific medication-related information
in an interoperable format.
• Assess the safety of medication use through active monitoring
and use these monitoring data to inform the implementation of
prevention strategies.
• Write prescriptions electronically by 2010. Also by 2010, all
pharmacies should be able to receive prescriptions electronically.
By 2008, all prescribers should have plans in place to implement
electronic prescribing.
• Subject prescriptions to evidence-based, current clinical deci-
sion support.
• Have the appropriate competencies for each step of the
medication-use process.
• Make effective use of well-designed technologies, which will
vary by setting.
ENORMOUS KNOWLEDGE DEFICITS MUST BE ADDRESSED

Current methods for generating and communicating information
about medications are inadequate and contribute to a growing rate of
medication errors. Likewise, error incidence rates, costs to the health
system, and prevention strategies are not well understood. As a result,
there are enormous gaps in the knowledge required to implement a safe
medication-use system.

SUMMARY 17
Risk/Benefit Information for Prescription Drugs

Being able to determine whether a medication error has been made
depends on knowing the correct dose of the drug for that patient at that
time and whether the indication for that drug is correct in comparison with
alternative approaches to treatment. Over the past several decades, how-
ever, drug evaluations have not been sufficiently comprehensive. As a re-
sult, the balance of risk and benefit for a drug frequently is not known for
a given population. Such gaps in therapeutic knowledge often result in
devastating effects on clinical practice and patient health, as exemplified by
adverse events involving hormone replacement therapy, cyclooxygenase-2
(COX-2) inhibitors, and nonsteroidal anti-inflammatory drugs that resulted
in increased morbidity and mortality.
These issues are magnified in specific patient populations. For example,
the majority of prescriptions written for children are off label—not based
on empirical demonstration of safety and efficacy. Among those over age
80, the fastest-growing segment of the population, almost nothing is known
about the balance of risks and benefits. Patients with renal dysfunction are
another large and growing group for whom more comprehensive studies
are needed. And patients with multiple comorbidities are typically excluded
from premarketing clinical trials, yet many of the major problems with
drug toxicity have occurred in those taking multiple medications because of
multiple diseases. Thus the numbers and types of patients for whom clinical
outcomes are measured must be greatly increased to elucidate the proper
dosing of drugs in individuals and within subgroups.
Of critical concern is the need for transparency through the publication
of clinical studies in a national repository to advance medication safety,
error prevention, and public knowledge. Such a repository should include
postmarket studies. The goal of such studies is to generate new data about
a drug’s effects in the population; often, however, these studies place insuf-
ficient emphasis on safety information. There is a need for comprehensive
redesign and expansion of the mechanisms for undertaking clinical studies
to improve understanding of the risks and benefits of drug therapies, pre-
vent errors and ADEs, and meet the health needs of the population.
Communication of Drug Information

How information about a drug is communicated to providers and con-
sumers can directly affect the frequency of medication errors and ADEs (see
Box S-6). Drug information is communicated through labeling and packag-
ing, marketing practices, and advertisements. Poorly designed materials
and inadequate representation of the risks and benefits to providers and
consumers have led to many errors, including inappropriate prescribing;

BOX S-6
Drug Naming, Labeling, and Packaging Problems
• Brand names and generic names that look or sound alike

• Different formulations of the same brand or generic drug
• Multiple abbreviations to represent the same concept
• Confusing word derivatives, abbreviations, and symbols
• Unclear dose concentration/strength designations
• Cluttered labeling—small fonts, poor typefaces, no background contrast,
overemphasis on company logos
• Inadequate prominence of warnings and reminders
• Lack of standardized terminology
confusion among products, affecting dispensing and administration; and

compromised ability to monitor the effects of drugs adequately.
In particular, drug names that look or sound alike increase the risk of
medication errors. Abbreviations, acronyms, certain dose designations, and
other symbols used for labeling also have caused errors. Even the layout
and presentation of drug information on the drug container or package
label can be visually confusing, particularly if it is designed for marketing
rather than clinical purposes.
Unit-of-use packaging—containers that provide enough medication for
a particular period, such as blister packs containing 30 individually wrapped
doses—is not widely employed in the United States but is used extensively
elsewhere. This form of packaging brings important safety and usage ben-
efits. The committee believes the expanded implementation of unit-of-use
packaging in this country warrants further investigation.
Another issue related to medication safety is the common practice of
providers offering free samples of prescription drugs to patients to start them
on their medications quickly, to adjust prescribed doses before the full pre-
scription is filled, and to offset medication costs for indigent and underinsured
patients. However, there has been growing unease about the way free samples
are distributed. In particular, concern exists about the resulting lack of docu-
mentation of medication use and the bypassing of standard prescribing and
dispensing services, which incorporate drug-interaction checking and phar-
macy counseling services. There is a need for resarch on the impact of differ-
ing sample distribution methods on medication safety.
Recommendation 4: Enhancing the safety and quality of the

medication-use process and reducing errors requires improved
methods for labeling drug products and communicating medica-
tion information to providers and consumers. For such improve-

SUMMARY 19
ments to occur, materials should be designed according to desig-

nated standards to meet the needs of the end user. Industry, AHRQ,
the FDA, and others as appropriate (e.g., U.S. Pharmacopeia, Insti-
tute for Safe Medication Practices) should work together to under-
take the following actions to address labeling, packaging, and the
distribution of free samples:
• The FDA should develop two guidance documents for indus-
try: one for drug naming and another for labeling and packaging.
The FDA and industry should collaborate to develop (1) a common
drug nomenclature that standardizes abbreviations, acronyms, and
terms to the extent possible, and (2) methods of applying failure
modes and effects analysis to labeling and packaging.
• Additional study of optimum designs for all drug labeling and
information sheets to reflect human and cognitive factors should be
undertaken. Methods for testing and measuring the effects of these
materials on providers and consumers should also be established,
including methods for field testing of the materials. The FDA, the
NLM, and industry should work with consumer and patient safety
organizations to improve the nomenclature used in consumer
materials.
• The FDA, the pharmaceutical industry, and other stakehold-
ers should collaborate to develop a strategy for expanding unit-of-
use packaging for consumers to new therapeutic areas. Studies
should be undertaken to evaluate different unit-of-use packaging
and design approaches that will best support various consumer
groups in their medication self-management.
• AHRQ should fund studies to evaluate the impact of free
samples on overall patient safety, provider prescribing practices,
and consumer behavior (e.g., adherence to the medication regi-
men), as well as alternative methods of distribution that can im-
prove safety, quality, and effectiveness.
Health Information Technology

Realization of the full benefits of many health information technologies
(such as decision-support systems, smart IV pumps, bar code administra-
tion systems, and pharmacy database systems) is hampered by the lack of
common data standards for system integration and well-designed interfaces
for end users.
Problems with data standards for drug information are threefold. First,
there is no complete, standardized set of terms, concepts, and codes to
represent drug information. Second, there is no standardized method for

presenting safety alerts according to severity and/or clinical importance.

Instead, providers are sometimes inundated with too many alerts, which
can result in “alert fatigue.” Third, many systems lack intelligent mecha-
nisms for relating patient-specific data to allowable overrides, such as those
associated with a particular patient and drug allergy alert or duplicate
therapy request.
The ability of clinicians to use health information technologies success-
fully depends on how well the technologies have been designed at the level
of human-machine interaction (i.e., the user interface). Displaying informa-
tion in a cluttered, illogical, or confusing manner leads to decreased user
performance and satisfaction. Moreover, a poorly designed user interface
can contribute to medication errors. Addressing user interface issues re-
quires greater attention to the cognitive and social factors influencing clini-
cians in their daily workflow and interaction with technologies (van Bemmel
and Musen, 1997).
Recommendation 5: Industry and government should collaborate

to establish standards affecting drug-related health information
technologies. Specifically:
• The NLM should take the lead in developing a common drug
nomenclature for use in all clinical information technology sys-
tems, based on standards for the national health information infra-
structure.
• AHRQ should take the lead in organizing mechanisms for
safety alerts according to severity, frequency, and clinical impor-
tance to improve clinical value and acceptance.
• AHRQ should take the lead in developing intelligent prompt-
ing mechanisms specific to a patient’s unique characteristics and
needs; provider prescribing, ordering, and error patterns; and
evidence-based best-practice guidelines.
• AHRQ should take the lead in developing user interface de-
signs based on the principles of cognitive and human factors and
the context of the clinical environment.
• AHRQ should support additional research to determine speci-
fications for alert mechanisms and intelligent prompting, as well as
optimum designs for user interfaces.
Research on Medication Errors:

Incidence Rates, Costs, and Prevention Strategies
In reviewing the research literature, the committee concluded that large
gaps exist in our understanding of medication error incidence rates, costs,

SUMMARY 21
and prevention strategies. The committee believes the nation should invest
about $100 million annually in the research proposed below.
The primary focus of research on medication errors in the next decade
should be prevention strategies, recognizing that to plan an error prevention
study, it is essential to be able to measure the baseline rate of errors. Evidence
on the efficacy of prevention strategies for improving medication safety is
badly needed in a number of settings, including care transitions, ambulatory
care (particularly home care, self-care, and medication use in schools), pedi-
atric care, psychiatric care, and the use of OTC and complementary and
alternative medications. For hospitals, key areas are further investigation of
some prevention strategies (particularly bar coding and smart IV pumps) and
how to integrate electronic health records with computerized provider order
entry, clinical decision support, bar coding, and smart IV pumps.
Overall, most data on medication error incidence rates come from the
inpatient setting, but the magnitude of the problem is likely to be greater
outside the hospital. Areas of priority for research on medication error and
ADE incidence rates are care transitions, specialty ambulatory clinics, psy-
chiatric care, the administering of medications in schools, and the use of
OTC and complementary and alternative medications. Much more research
is needed as well on the patient’s role in the prevention of errors, specifi-
cally, what systems provide the most cost-effective support for safe and
effective medication self-management or for surrogate participation in medi-
cation use when a patient is unable to self-manage.
Most studies of the costs of medication errors relate to hospitals, and
some report data more than 10 years old (Bates et al., 1997). A better
understanding of the costs and consequences of medication errors in all
care settings is needed to help inform decisions about investing in medica-
tion error prevention strategies.
Recommendation 6: AHRQ should take the lead, working with

other government agencies such as CMS, the FDA, and the NLM,
in coordinating a broad research agenda on the safe and appropri-
ate use of medications across all care settings, and Congress should
allocate the funds necessary to carry out this agenda. This agenda
should encompass research methodologies, incidence rates by type
and severity, costs of medication errors, reporting systems, and in
particular, further testing of error prevention strategies.
OVERSIGHT, REGULATION, AND PAYMENT

Improving medication safety will require key changes in oversight, regu-
lation, and payment. Accordingly, the following recommendation is ad-
dressed to the stakeholders that shape the environment in which care is

delivered, including legislators, regulators, accreditors, payers, and patient

safety organizations.3
Recommendation 7: Oversight and regulatory organizations and

payers should use legislation, regulation, accreditation, and pay-
ment mechanisms and the media to motivate the adoption of prac-
tices and technologies that can reduce medication errors, as well as
to ensure that professionals have the competencies required to de-
liver medications safely.
• Payers and purchasers should continue to motivate improve-
ment in the medication-use process through explicit financial
incentives.
• CMS should evaluate a variety of strategies for delivering
medication therapy management.
• Regulators, accreditors, and legislators should set minimum
functionality standards for error prevention technologies.
• States should enact legislation consistent with and comple-
mentary to the Medicare Modernization Act’s electronic prescrib-
ing provisions and remove existing barriers to such prescribing.
• All state boards of pharmacy should undertake quality im-
provement initiatives related to community pharmacy practice.
• Medication error reporting should be promoted more aggres-
sively by all stakeholders (with a single national taxonomy used for
data storage and analysis).
• Accreditation bodies responsible for the oversight of profes-
sional education should require more training in improving medi-
cation management practices and clinical pharmacology.
MOVING FORWARD
The American people expect safe medication care. In this report, the
committee proposes an ambitious agenda for making the use of medica-
tions safer. This agenda requires that all stakeholders—patients, care pro-
viders, payers, industry, and government, working together—commit to
preventing medication errors. Given that a large proportion of injurious
drug events are preventable, this proposed agenda should deliver early and
measurable benefits.
3Patient safety organizations are regulated through the Patient Safety and Quality Improve-
ment Act of 2005 (P.L. 109-41). Broadly, they are organizations separate from health care
providers that collect, manage, and analyze patient safety data, and advocate safety improve-
ments on the basis of analysis of the patient safety data they receive.

SUMMARY 23
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Appendix F
Committee Biographies
COMMITTEE ON THE ASSESSMENT OF

THE US DRUG SAFETY SYSTEM
Sheila Burke (Chair), MPA, RN, is deputy secretary and chief operating of-
ficer of the Smithsonian Institution. Ms. Burke is also the vice chair of the
Robert Wood Johnson Health Policy Fellowships Board. She is a member of
the Medicare Payment Advisory Commission and serves as chair of the Kai-
ser Family Foundation, the Kaiser Commission on the Future of Medicaid
and the Uninsured, WellPoint Health Networks, Chubb Corporation, and
the University of San Francisco. She is an adjunct lecturer in public policy
at the Kennedy School of Government, Harvard University. She previously
was executive dean and a lecturer in public policy at Harvard University’s
John F. Kennedy School of Government. From 1986 to 1996, Ms. Burke
was chief of staff to Senate Majority Leader Robert Dole. In 1995, she
was also elected to serve as secretary of the Senate. Before joining Senator
Dole’s personal office, she served the Senate Committee on Finance as a
professional staff member and as deputy staff director. Early in her career,
she worked as a staff nurse in Berkeley, California, and was director of
program and field services for the National Student Nurses Association in
New York. She received her MPA from Harvard University and her BS in
nursing from the University of San Francisco. Ms. Burke is a member of the
Institute of Medicine.
David Blumenthal, MD, MPP, is the Samuel O. Thier Professor of Medicine

and Professor of Health Care Policy at Harvard Medical School and direc-
309

tor of the Institute for Health Policy at Massachusetts General Hospital

and Partners HealthCare System. Dr. Blumenthal is also the director of the
Harvard University Interfaculty Program for Health Systems Improvement.
Harvard University receives about $1 million per year from the Merck
Foundation to support the research and convening activities of the Program
for Health System Improvement. Dr. Blumenthal serves on several editorial
boards, including those of the American Journal of Medicine and the Journal
of Health Politics, Policy and Law. He is a national correspondent for the
New England Journal of Medicine. Dr. Blumenthal was the founding chair-
man of AcademyHealth (formerly the Academy for Health Services Research
and Health Policy), the national organization of health services researchers,
and is a member of its board of directors. During the late 1970s, he was a
professional staff member on Senator Edward Kennedy’s Subcommittee on
Health and Scientific Research. Dr. Blumenthal previously was the chair of
the Institute of Medicine (IOM) Committee on Department of Veterans Af-
fairs Pharmacy Formulary Analysis. His research interests include academic-
industrial relationships in the life sciences, quality management in health
care, the role and influence of health information technology, determinants
of physician behavior, and access to health services. He received his MD
and his MPP from Harvard University. Dr. Blumenthal is a member of the
IOM.
Sir Alasdair Breckenridge, CBE, is chairman of the UK Medicines and

Healthcare Products Regulatory Agency (MHRA). MHRA is the executive
agency of the UK Department of Health that is responsible for protecting
and promoting public health and patient safety by ensuring that medicines,
healthcare products, and medical equipment meet appropriate standards of
safety, quality, performance, and effectiveness and are used safely. In 2004,
he was awarded a knighthood for his service to medicine in recognition of
his role in ensuring that British patients receive safe medical treatment. Prof.
Breckenridge has played a leading role in monitoring the safety of medicines
for many years. He previously was the chairman of the UK Committee on
the Safety of Medicines (CSM) and was a member of the CSM Adverse
Reactions Group and the Subcommittee on Adverse Reactions to Vaccines
and Immunisation. He is a former professor of clinical pharmacology at
the University of Liverpool and headed its Department of Pharmacology
and Therapeutics for 26 years. Prof. Breckenridge has been both a member
and chairman of a regional health authority and a member of a local health
authority. His research interests include the pharmacology of HIV drugs.
R. Alta Charo, JD, is the Warren P. Knowles Professor of Law and Bioethics
at the University of Wisconsin Law School and its Medical School’s Depart-
ment of Medical History & Bioethics. She teaches in the areas of Food and

APPENDIX F 311
Drug Administration law, biotechnology law, bioethics, and reproductive

rights. In addition, she has served on the UW Hospital clinical-ethics com-
mittee, the UW institutional review board for the protection of human
subjects in medical research, and the UW Bioethics Advisory Committee.
Prof. Charo is the author of nearly 100 articles, book chapters, and govern-
ment reports on such topics as voting rights, environmental law, medical-
genetics law, reproductive rights law, science policy and bioethics. She is a
member of the board of directors of the Alan Guttmacher Institute and the
program board of the American Foundation for AIDS Research (amfAR).
She serves on several expert advisory boards of organizations with an inter-
est in stem-cell research, including WiCell and the California Institute for
Regenerative Medicine. She has served as a consultant to the Institute of
Medicine (IOM) and the National Institutes of Health (NIH) former Office
of Protection from Research Risks. In 1994, Prof. Charo served on the NIH
Human Embryo Research Panel, and from 1996–2001, on the presidential
National Bioethics Advisory Commission where she participated in draft-
ing its reports on such topics as cloning, stem cell research, and research
ethics. She is a member of the National Research Council (NRC) Board on
Life Sciences and the IOM Board on Population Health and Public Health
Practices. She currently co-chairs the NRC-IOM Human Embryonic Stem
Cell Research Advisory Committee.
Susan Edgman-Levitan, PA, is executive director of the John D. Stoeckle Cen-

ter for Primary Care Innovation at Massachusetts General Hospital (MGH).
She is a lecturer in the Department of Medicine of Massachusetts General
Hospital and an associate in health policy at Harvard Medical School. Be-
fore going to MGH, Ms. Edgman-Levitan was the founding president of the
Picker Institute. She has been the coprincipal investigator on the Harvard
Consumer Assessment of Health Plans Study (CAHPS) from 1995 to the
present, which is funded by the Agency for Healthcare Research and Quality.
She has served as chair of the Institute for Healthcare Improvement (IHI)
Breakthrough Series Collaborative on Improving Service Quality and is the
IHI fellow for patient and family-centered care. She is an editor of Through
the Patient’s Eyes (a book on creating and sustaining patient centered care),
The CAHPS Improvement Guide, and has written many papers and other
publications on patient-centered care. She serves on several boards, including
those of the National Patient Safety Foundation (NPSF), the Center for In-
formation Therapy, the Foundation for Informed Medical Decision Making,
Planetree, and the American Academy on Physician and Patient. She has co-
chaired the annual NPSF congress on patient safety since 2002. She received
the Distinguished Alumni Award from the Duke Physician Assistant Program
and was inducted into the Duke University Medical Center Hall of Fame in
2004. She received her PA degree from Duke University.

Susan Ellenberg, PhD, is professor of biostatistics and associate dean for

clinical research at the University of Pennsylvania School of Medicine.
Previously, Dr. Ellenberg was director of the Office of Biostatistics and
Epidemiology at the Center for Biologics Evaluation and Research of the
Food and Drug Administration (FDA), chief of the Biostatistics Research
Branch in the Division of AIDS of the National Institute of Allergy and In-
fectious Diseases, and mathematical statistician in the Biometrics Research
Branch of the Cancer Therapy Evaluation Program at the National Cancer
Institute. Before her federal government service, she had positions at the
EMMES Corporation and the George Washington University. She serves as
associate editor of Clinical Trials and of the Journal of the National Cancer
Institute. Dr. Ellenberg is a fellow of the American Statistical Association
and the American Association for the Advancement of Science and an
elected member of the International Statistical Institute. Her recent book on
clinical trials data monitoring committees, of which Thomas Fleming (Uni-
versity of Washington) and David DeMets (University of Wisconsin) were
coauthors, was named WileyEurope Statistics Book of the Year for 2002.
Dr. Ellenberg’s research interests include issues in the design and analysis of
clinical trials and assessment of medical product safety, particularly focus-
ing on efficient trial designs, interim monitoring and the operation of data
monitoring committees, evaluation of surrogate endpoints, ethical issues in
clinical research, and special issues in trials of cancer and AIDS therapies
and of vaccines. She serves on two National Institutes of Health-sponsored
data monitoring committees, and one for Curagen. She received her PhD in
mathematical statistics from George Washington University.
Robert D. Gibbons, PhD, is a professor of biostatistics and psychiatry and

director of the Center for Health Statistics at the University of Illinois at
Chicago. He received his doctorate in statistics and psychometrics from
the University of Chicago in 1981. He received a Young Scientist Award
from the Office of Naval Research (1981), a Career Scientist Award from
the National Institutes of Health (NIH) (1995), and numerous other NIH
grants. His research spans medical, biologic, and environmental statistics,
with emphasis on statistical problems in mental health, health services re-
search, longitudinal data analysis, and environmental regulatory statistics.
Dr. Gibbons is a fellow of the American Statistical Association and received
two the Youden Prizes for statistical contributions to chemistry and the Har-
vard Award for contributions to psychiatric epidemiology and biostatistics.
Dr. Gibbons has served on several Institute of Medicine (IOM) committees,
including the Committee on Halcion and the Committee on Organ Procure-
ment and Transplantation, and served on the IOM Board on Health Sciences
Policy. He has written over 150 peer-reviewed papers and four books. Dr.
Gibbons recently has conducted statistical work focusing on the reanalysis

APPENDIX F 313
of data on selective serotonin reuptake inhibitors and suicide. Dr. Gibbons

is a member of the IOM.
George Hripcsak, MD, MS, is professor and vice chair of Columbia Univer-
sity’s Department of Biomedical Informatics, associate director of medical
informatics services for New York-Presbyterian Hospital, and senior infor-
matics advisor at the New York City Department of Health and Mental
Hygiene. He led the effort to create the Arden Syntax, a language for repre-
senting health knowledge that has become a national standard. His Applied
Informatics project—funded by the US Department of Commerce to link the
medical center, a home care agency, and the New York City Department of
Health to improve inner-city tuberculosis care—won the National Informa-
tion Infrastructure award. Dr. Hripcsak’s current research focus is on the
clinical information stored in electronic medical records. Using data mining
techniques, such as machine learning and natural language processing, he is
developing the methods necessary to support clinical research and patient
safety initiatives. Dr. Hripcsak was a elected fellow of the American College
of Medical Informatics in 1995 and served on the Board of Directors of the
American Medical Informatics Association (AMIA). As chair of the AMIA
Standards Committee, he coordinated the medical-informatics community
response to the Department of Health and Human Services for the health-
informatics standards rules under the Health Insurance Portability and Ac-
countability Act of 1996. He chaired the Biomedical Library and Informat-
ics Review Committee of the National Library of Medicine through 2005.
He is associate editor of the Journal of the American Medical Informatics
Association and of Computers in Biology and Medicine, and he is an edito-
rial board member of the Journal of Biomedical Informatics. He received
his MD and his MS in biostatistics from Columbia University.
David Korn, MD, is senior vice president for biomedical and health sciences
research at the Association of American Medical Colleges. He served as
Carl and Elizabeth Naumann Professor and dean of the Stanford University
School of Medicine from 1984 to 1995, and as vice president of Stanford
University from 1986 to 1995. Earlier, he had served as professor and chair-
man of the Department of Pathology at Stanford from 1968. Dr. Korn was
appointed by President Ronald Reagan as chairman of the National Cancer
Advisory Board from 1984 to 1991. He has been chairman of the Stanford
University Committee on Research, president of the American Association
of Pathologists (now the American Society for Investigative Pathology),
president of the Association of Pathology Chairmen; member of the Board
of Directors and the Executive Committee of the Federation of American
Societies for Experimental Biology, and member of the Board of Directors of
the Association of Academic Health Centers. He was also a founder of the

California Transplant Donor Network, the Clinical Research Roundtable of

the Institute of Medicine (IOM), and the Association for the Accreditation
of Human Research Protection Programs. Dr. Korn has been a member of
the editorial boards of the American Journal of Pathology, The Journal of
Biological Chemistry, and Human Pathology, and for many years he was an
associate editor of the latter. He received his MD from Harvard University.
Dr. Korn is a member of the IOM.
David O. Meltzer, MD, PhD, is associate professor of medicine and affili-

ated faculty of the Department of Economics and Graduate School of Public
Policy at the University of Chicago. He is director of the Center for Health
and Social Sciences and the Centers for Disease Control and Prevention’s
Chicago Center of Excellence in Health Promotion Economics at the
University of Chicago. He is codirector of the Section of General Internal
Medicine research program, the Robert Wood Johnson Clinical Scholars
Program, and the MD/PhD Program in the Social Sciences at the University
of Chicago. Dr. Meltzer is a faculty research fellow for the National Bu-
reau of Economic Research. His awards include the Lee Lusted Prize of the
Society for Medical Decision Making, the Health Care Research Award of
the National Institute for Health Care Management, the Young Investiga-
tor Award of the Society for Hospital Medicine, the Robert Wood Johnson
Generalist Physician Award, the Eugene Garfield Economic Impact Award
from Research America, and the Leaders in General Medicine Award from
the Midwest Society for General Internal Medicine. Dr. Meltzer’s research
interests include the theoretical foundations of medical cost-effectiveness
analysis, the effects of medical specialization and prospective payment
systems on the cost and quality of care, and the effects of Food and Drug
Administration regulation on innovation in the pharmaceutical industry.
He is completing work on a small grant from TAP Pharmaceuticals on risk
factors for gastrointestinal bleeding and on a small grant from a consortium
of pharmaceutical companies on methods to assess the cost effectiveness of
treatment for diabetes. The Center for Health and the Social Sciences at the
University of Chicago received about $25,000 from the Merck Foundation
last year for general support. Dr. Meltzer received his MD and PhD in eco-
nomics from the University of Chicago.
Woodrow A. Myers, Jr., MD, MBA, is the former executive vice president
and chief medical officer of WellPoint Health Networks. Dr. Myers man-
aged WellPoint’s Healthcare Quality Assurance Division, including medical
policy, clinical affairs, and health services operations. He was also respon-
sible for strategic initiatives designed to enhance the healthcare experience
for the company’s members and to simplify administration and improve
communications with physicians and other healthcare professionals. Be-

APPENDIX F 315
fore joining WellPoint, he was director of healthcare management at Ford

Motor Company. Dr. Myers also served as the corporate medical director
for Anthem Blue Cross Blue Shield, commissioner of health for the state of
Indiana, and commissioner of health for New York City. During the time
Dr. Myers served as the commissioner of health in the State of Indiana, he
advocated on behalf of Ryan White, a young boy afflicted with HIV who
wanted to attend school. After a laborious process, Dr. Myers helped to
change the law so that Indiana became the sole determiner of who attended
school, thereby setting an important legal precedent. Earlier in his career, he
was an assistant professor of medicine at the University of California San
Francisco and a fellow in critical care medicine at the Stanford University
Medical Center. Dr. Myers has received numerous medical and community-
service awards and has published extensively on medical issues important
to public health. He has served on the Board of Directors of the Stanford
Hospital and is a former university trustee. He served as a member of the
Harvard University Board of Overseers. He received his MD from Harvard
University and his MBA from Stanford University. Dr. Myers is a member
of the Institute of Medicine.
Mary K. Olson, PhD, is an associate professor of economics and political

economy at Tulane University. Before working at Tulane University, she was
associate professor of health policy and administration in the Yale University
School of Medicine Department of Epidemiology and Public Health. Dr.
Olson has expertise on Food and Drug Administration (FDA) regulation.
She has published articles that examine new-drug approval policies, FDA
enforcement strategies, FDA advisory committees, the effects of prescrip-
tion drug user fees on FDA, the effects of faster drug reviews on the safety
of new medicines, and the risks associated with novel and less novel drugs.
Her research interests include pharmaceutical regulation and new drug
safety, and gender-related risks among newly approved drugs. Dr. Olson is
completing work on a small grant from the Agency for Healthcare Research
and Quality for a project to examine the association between the length of
FDA review times and adverse drug reaction counts among the 1990–1998
new-drug approvals. Dr. Olson received her PhD in political economics from
Stanford University.
Bruce M. Psaty, MD, PhD, is a professor of medicine, epidemiology, and

health services, and co-director of the Cardiovascular Health Research
Unit, University of Washington, Seattle, and an affiliate investigator in the
Center for Health Studies at Group Health, Seattle, WA. He is the principal
investigator on four large epidemiologic studies and has had a major roles in
National Institutes of Health (NIH)-funded multi-center studies, including
the Cardiovascular Health Study, the Multi-Ethnic Study of Atherosclerosis,

and the Women’s Health Initiative. He is the chair of the NIH Cardiovascu-
lar Disease and Sleep Epidemiology Study Section and chair of the Group
Health Research Committee. Earlier in his career, he was a Robert Wood
Johnson Clinical Scholar at the University of Washington. Dr. Psaty is a
member of the American Epidemiological Society as well as the American
Heart Association Council on Epidemiology and Prevention. In 2005, he
received the University of Washington Outstanding Public Service award.
He publishes regularly in peer-reviewed journals, including many articles
and editorials on the risks and benefits of a variety of drug therapies. Dr.
Psaty’s research interests include cardiovascular epidemiology, drug safety,
hypertension, epidemiologic methods, pharmacogenetics, and pharmacoepi-
demiology. He has served on three NIH-funded data monitoring commit-
tees. He received his MD and PhD from Indiana University and his MPH
from the University of Washington.
Christopher H. Schroeder, MDiv, JD, is Charles S. Murphy Professor of Law

and Public Policy Studies and Director of the Program in Public Law at Duke
University Law School. He has served as acting assistant attorney general in
the Office of Legal Counsel in the US Department of Justice, and as Chief
Counsel to the Senate Judiciary Committee. He teaches environmental law;
government, business, and public policy; environmental litigation; toxic-
substances regulation; and philosophy of environmental protection. He has
written on the philosophic foundations of risk regulation and liability, the
regulation of toxic substances, American environmental policy, and a variety
of topics in public law and theory. He is coauthor of a leading environmental-
law casebook (5th edition, 2006), Environmental Regulation: Law, Science,
and Public Policy. His most recent book is A New Progressive Agenda for
the Public Health and the Environment (2005), coedited with Rena Steinzor.
His research interests include risk regulation, democratic theory, legislative
institutions and separation of powers. Mr. Schroeder received his BA from
Princeton University, his MDiv from Yale University, and his JD from the
University of California, Berkeley.
Andy Stergachis, PhD, MS, RPh, is professor of epidemiology, adjunct

professor of pharmacy and the former interim chairman of the Department
of Pathobiology in the School of Public Health and Community Medicine,
University of Washington. He was chairman of the University’s Department
of Pharmacy and director of the Program in Pharmaceutical Outcomes Re-
search and Policy. He is affiliated with the University’s Northwest Center for
Public Health Practice. Dr. Stergachis has served on the National Institutes
of Health Epidemiology and Disease Control Study Section, the Agency for
Healthcare Research and Quality Health Systems Research Study Section,
committees of the National Committee on Quality Assurance, and the

APPENDIX F 317
Institute of Medicine’s Committee on Poison Prevention and Control and

Committee to Study the Interactions of Drugs, Biologics, and Chemicals in
the US Military. He held several positions with Group Health Cooperative
of Puget Sound and served on its Pharmacy and Therapeutics Committee
and the board of the Group Health Community Foundation. In 1998, he
joined drugstore.com and served as vice president and chief pharmacist;
now serves as pharmacy adviser. He cofounded and served as principal of
Formulary Resources and serves as a consultant on managed care pharmacy
for that company. Dr. Stergachis was consultant to United HealthCare
for its pharmacoepidemiology cooperative agreement with the Food and
Drug Administration. He was the 1990 American College of Preventive
Medicine/Burroughs Wellcome Scholar in Pharmacoepidemiology. The
American Association of Pharmaceutical Research Scientists awarded Dr.
Stergachis the 1994 Research Achievement Award in Economic, Marketing
and Management Sciences. In 1999, he was selected as one of the 50 Most
Influential Pharmacists in the United States by American Druggist. He was
awarded the 2002 Pinnacle Award by the American Pharmaceutical Associa-
tion Foundation. He serves as board member of the American Pharmacists
Association Foundation and he is a fellow in the International Society for
Pharmacoepidemiology. He received his PhD and MS from the University
of Minnesota and his BPharm from Washington State University.


Index
A recommendations concerning, 9–10,

12, 133–134, 188–189
AAMC. See Association of American timeline for planning meetings of, 45
Medical Colleges Advocacy movements, 177
Abbreviated NDAs, 32 for AIDS treatment, 22, 75
“Academic detailing,” 183 AE. See Adverse event reporting
Academic research enterprise, 2, 5, 28, 146. AERS. See Adverse Event Reporting System
See also Professional societies The agency. See Food and Drug
Accelerated approval, 165 Administration
Accountability, by the FDA, need for greater, 4 Agency for Healthcare Research and
Accutane, 120 Quality (AHRQ), 21, 25, 113, 180,
ACE inhibitors, 38 183, 212
Adverse drug reactions AIDS treatment advocacy movement, 22, 75
monitoring, 98 ALLHAT. See Antihypertensive and Lipid-
Adverse event (AE) reporting, 54, 167 Lowering Treatment to Prevent
background incidence of, 114 Heart Attack Trial
electronic submission of, 109 Alosetron (Lotronex), 59
prevalence of, 113 Amlodipine, 115
recommendations concerning, 7, Antidepressants, warnings added to labels
114–115 on, 17, 50
substantial under-reporting, 55, 109 Antihypertensive and Lipid-Lowering
Adverse Event Reporting System (AERS), Treatment to Prevent Heart Attack
53–56, 98, 157, 184 Trial (ALLHAT), 115
Advertising. See Direct-to-consumer Appropriations
advertising; Pharmaceutical as source of FDA funding, 13, 19, 23,
advertising 118, 193, 196, 198
Advisory committees, 44–46, 179, 211 Approval process, 27
on communication with the public, 188 accelerated, 165
and the credibility of safety science, confirmatory studies, 115–119
131–142 safety signal generation, 108–110
319

safety signal strengthening and testing, Celecoxib, 17

110–115 Center for Biologics Evaluation and
shortening, 107–119 Research (CBER), 49, 129, 188
speed of, 16 Center for Devices and Radiological Health
APPROVe trials, 55 (CDRH), 188
Association of American Medical Colleges Center for Drug Evaluation and Research
(AAMC), 142, 211 (CDER), ix–x, 15, 21, 31, 46–47,
Automated healthcare databases, 7, 49, 65, 105, 179, 193–202,
114–115 205. See also Organizational
Azidothymidine (AZT), 37 dysfunction in the CDER culture;
Solutions proposed for CDER’s
organizational dysfunction
B credibility of, 85
history of funding, 194
Bain report, 32 IT needs within, 202
Bayesian analysis, 109–110 organizational culture in, 4, 66
Best Pharmaceuticals for Children Act, 57, press coverage of internal problems in,
152, 165 2
“Best practices,” disseminating, 87–88 recommendations concerning review
Bias, intellectual, 141 teams, 10, 146–147
Biologics license application (BLA) relevant changes at, 210
submissions, 42 shepherding products through trials,
numbers of new approvals, 42 154
Biotechnology Industry Organization (BIO), staffing, 195, 199–200
88 Center for Outcomes and Evidence, 212
Bioterrorism and Preparedness and Centers for Disease Control and Prevention
Response Act, 23 (CDC), 81, 112, 128
BLA. See Biologics license application Centers for Education and Research on
submissions Therapeutics (CERTs), 109
Black box warnings, 50, 58–59 Centers for Medicare and Medicaid Services
Black triangle, 170–171 (CMS), 21, 25, 115, 180–181, 201
Booz Allen Hamilton, 211 Central Hudson Gas & Electric Corp.
Boston Consulting Group, 123 v. Public Service Commission,
British National Formulary, 170 159–160
Bromfenac, 38 Cerivastatin, 17, 109
Bureau of Labor Statistics, 92 CERTs. See Centers for Education and
Bush, President George W., 88, 207 Research on Therapeutics
CFR. See Code of Federal Regulations
Changes at the FDA
C during course of study, 205–215
C-Path Institute, 213 Critical Path Initiative and
Calcium-channel blockers, 115 partnerships, 212–213
Cardiovascular risks, 112, 116 Drug Safety Initiatives, 205
CBER. See Center for Biologics Evaluation Drug Safety Oversight Board, 205–206
and Research Drug Watch Web page, 206
CDC. See Centers for Disease Control and labeling, 210
Prevention leadership changes in the FDA,
CDER. See Center for Drug Evaluation and 207–208
Research other relevant changes at the FDA and
CDRH. See Center for Devices and CDER, 210
Radiological Health program reviews or evaluations,
211–212

INDEX 321
recent materials from the FDA, improving, 187–190

208–209 between providers and the drug safety
structural changes and leadership system, 181–184
changes in the CDER, 206–207 between the public and the drug safety
Changes in the broad context of drug system, 178–179
regulation, 19–21 recommendations concerning, 12–13,
The charge (to the committee), 21–24 188–189
defining and meeting, 21–28 roles and needs of providers and
disclaimers, 24–25 patients, 178–184
the shifting landscape of drug safety, 26 structure needed to support an
study process, 25–26 effective drug safety system, 4
toward a new vision of drug safety, Confirmatory studies, 143n
26–28 reducing uncertainty about risk and
Chlorthalidone, 115 benefit after approval, 115–119,
Cisapride, 50, 109, 168 122
Citizens’ Advisory Committee, 130 Conflict of interest (COI) considerations,
Clinical development, PDUFA goal for, 42 45, 86, 93, 134–142
Clinical holds, 154 appearance of, 73
Clinical investigation (phase 2) studies, 35 “cover memos” regarding, 135–139
Clinical pharmacology (phase 1) studies, 35 recommendations concerning, 141–142
Clinical review templates, in postmarketing, zero-tolerance policy regarding,
79–80 140–141
Clinical trials, 76, 153 Congress, 2, 4, 8, 48, 66, 69, 95, 97,
early, and related studies, 34–35 117–119, 153
formal (phase 3), 35 ensuring that CDER receives needed
in IND submission and review, and authority and assets, x, 18
their limitations, 37–39 periodic reports to, 23, 71, 197, 202
premarket, 38 recommendations to, 6–8, 11–13, 98–
recommendations regarding, 10, 100, 117–119, 169–172, 197–203
144–145 “Consults,” 78–79, 82
clinicaltrials.gov, 143, 145 Consumer Bill of Rights, 177
Clozapine, 168 Consumer medication information,
CMS. See Centers for Medicare and 185–187
Medicaid Services criteria for useful, 187
Code of Federal Regulations (CFR), 153, Consumer Price Index, 23
159 Consumer Product Safety Commission, 114
COI. See Conflict of interest considerations Consumers. See also AIDS treatment
Commissioner of the FDA, 5–6, 9, advocacy movement; The public
92–93, 131. See also individual empowering, 20
commissioners organizations of, 4, 66
instability in the office of, 5, 88–89 representatives of, 179
Committee on Identifying and Preventing Council of Public Representatives (COPR),
Medication Errors, 24 190
Committee on Patient Education, 187 “Cover memos” regarding COI
Committee on the Assessment of the US considerations, 135–139
Drug Safety System, 2, 17, 65, 105, CPI. See Critical Path Initiative
178 Crawford, Acting FDA Commissioner
charge to, 21–24 Lester M., 207
Communication about safety, 27, 177–192 Credibility of safety science, 126–147
FDA’s challenges in, 4, 184–190 advisory committees, 131–142
how industry communicates to the expertise in the CDER, 127–131
public and patients, 184, 188 transparency, 142–147

Critical Path Initiative (CPI), 33, 70n, 105, Development cost, of drugs, 32
201, 207, 211–213 DHEW. See Department of Health,
report on, 20 Education, and Welfare
Critical Path Opportunities Report, 212–213 DHHS. See Department of Health and
Culture of safety in CDER, 27, 65–104 Human Services
difficulties changing, 90 Dietary supplements, 153
the external environment, 68–75 Differing professional opinion (DPO)
organizational challenges, 65–100 procedure, 47n
solutions proposed for CDER’s Direct-to-consumer (DTC) advertising, 21,
organizational dysfunction, 90–100 52–53, 158–164, 167, 171–172
structural factors, policies, and court challenges to restricting, 159
procedures, 75–90 deterrence of excessive, 198
need for more robust standards of
assessment, 189
D recommendations concerning, 11–12,
169–172
“DailyMed” health information Director’s Consumer Liaison Group
clearinghouse, 210 (DCLG), 190
Data management, 39–40 Disagreement in the face of uncertainty, 127
Databases nurturing a culture that values, 94
automated, 56 scientific, 85–87
mining, 57, 157 Discipline reviews, 79
DCLG. See Director’s Consumer Liaison different perspectives of, 86
Group Disclaimers, 24–25
DDMAC. See Division of Drug Marketing Disclosure requirements, 141
and Communication Dispute resolution, 84
DDRE. See Division of Drug Risk Evaluation in NDAs, 47–48
“Dear Health Practitioner” letters, 58, 158 Division of Drug Marketing and
DEcIDE. See Developing Evidence Communication (DDMAC), 52,
to Inform Decisions about 78, 159, 163, 179
Effectiveness Network “DDMAC Watch,” 162
Decision-making Division of Drug Risk Evaluation (DDRE),
concerning postmarket safety of a 32, 36, 51, 56
drug, ix, 47 Division of Neurology Products (DNP), 36
political considerations in, 90 DoD. See Department of Defense
regulatory, by the FDA, ix DPO. See Differing professional opinion
science-based, 66, 129 procedure
Department of Defense (DoD), 118 Drug approval process
Department of Health and Human Services limitations on, 59
(DHHS), 2, 18, 41, 71, 74n, 93n, pressure to speed up, 22, 40
113, 153, 180, 205. See also Drug Development Science Obstacles and
Secretary of Health and Human Opportunities for Collaborations,
Services 211
Department of Health, Education, and Drug industry. See Pharmaceutical industry
Welfare (DHEW), 74n Drug Price Competition and Patent Term
Department of Veterans Affairs (VA), 21,
Extension Act, 152
92, 112–113, 201 Drug Regulation Reform Act, 156
“Detailing,” 18, 158, 183–184 Drug safety
academic, 183 communication about, 27, 177–192
Developing Evidence to Inform Decisions culture of safety in CDER, 27
about Effectiveness (DEcIDE) experts in, 66
Network, 113, 180

INDEX 323
regulatory process and agency able to promotion and information,

protect the public health, 27 postmarket, 52–53
rigorous science of, 27 promotion to patients greatly
the shifting landscape of, 26 increased, 21
toward a new vision of, 26–28 DSaRM. See Drug Safety and Risk
warning the public about risks, 1 Management Advisory Committee
Drug safety activities, actionable DSB. See Drug Safety Oversight Board
performance goals for, 97 DTC advertising. See Direct-to-consumer
Drug Safety and Risk Management advertising
(DSaRM) Advisory Committee, 46,
87, 112, 133–134, 187
Drug Safety Initiative, 205 E
Drug Safety Management Board, 144
Economic impact of drugs, 32
Drug Safety Oversight Board (DSB), 47, 82,
Electronic medical records, 117
86–87, 99, 185, 187–188, 205–206
Electronic submission, of adverse event
Drug safety system, 3–4, 17
reports, 109
committee convened to assess, 2
“End of phase 2 meeting,” in IND
communicating with providers,
submission and review, 35–36
181–184
Enforcement tools, 163, 166–167
communicating with the public,
decisions about, 58
178–179
Enhancing Drug Safety and Innovation Act,
communication structure needed to
201n
support effectively, 4
Environmental Protection Agency, 197n
financial resources required to enable
Epidemic Intelligence Service program, 128
CDER to support the FDA mission,
Epidemiologic studies, 76, 86, 115, 201
4
Epidemiologists, safety teams of, 88
impairment in, 4
European Medicines Agency, 54, 158, 173,
organizational culture of CDER, 4
211
regulatory authority necessary to
Evaluation of FDA’s First Cycle Review
provide for drug safety, 4
Performance—Retrospective
regulatory science and processes
Analysis, 209
necessary to enhance drug safety, 4
Exceptions, in FDA’s regulatory authority,
resources for, 4–5, 13–14, 166,
165
193–204
Expectations of multiple constituencies,
Drug Watch Web site, 57, 99, 179, 185,
conflicting, 69
187, 205–206
Expertise
Drugs. See also New drugs; Prescription
in the CDER, and the credibility of
drugs; Sponsors of drugs; individual
safety science, 127–131
drugs cited
in preapproval evaluation for the
conditions linked to, 54
PDUFA IV, 98
cost of, 178
External environment in CDER’s
development costs, 32
organizational dysfunction, 68–75,
effectiveness of, 107
97–100
generics, 159
the FDA-industry interface, 70–75
life-saving for specific patients, 1
“lifestyle,” 21
mechanisms of action, 2
milestones in lifecycle of, 167 F
over-the-counter, 90 Fast track studies, 39
pediatric, 165 FDA. See Food and Drug Administration
potential benefit of, 34 FDA Science Board, 129

FDAMA. See Food and Drug response to public meeting input, 185
Administration Modernization Act Science Board, 129
FD&C. See Food, Drug, and Cosmetic Act Food and Drug Administration (FDA)
Federal Advisory Committee Act, 116, 146, authority, 51, 151. See also Direct-
190 to-consumer (DTC) advertising;
Federal advisory committees, on consumer Strengthening FDA’s regulatory
issues, examples of, 190 authority
Federal Aviation Administration, after approval, 155–164
organizational problems at, 67, 91 to compel completion of
Federal Communications Commission, 92, postmarketing commitments,
197n 155–157
Federal Register, 45, 156, 161, 186 exceptions in, 165
Federal Trade Commission (FTC), 160 guidance documents, 41, 208–209
Financial resources. See Resources for the oversight of sponsor promotional
drug safety system activities, 158–164
First Amendment protections, of truthful preapproval, 37, 154–155
commercial speech, 159, 161–162, recommendations concerning, 11, 170
171, 183 to unilaterally impose risk-reducing
Food and Drug Administration (FDA), remedies, such as label changes and
ix–x, 1–12, 15, 23–25, 65, 105, distribution restrictions, 157–158
177, 180–181, 205. See also Food and Drug Administration
Commissioner of the FDA; Recent Modernization Act (FDAMA), 143,
FDA materials 152, 156
approval but not a lifetime guarantee, 2 Food, Drug, and Cosmetic (FD&C) Act, 16,
challenges in communicating to the 22–23, 48, 51, 69, 90, 152, 156,
public and patients, 184–190 159, 184
consumer medication information Drug Amendments to, 16, 152
from, 185–187 Food Research Laboratory, 129
credibility of, 4–5, 70, 85, 88, 132 FTC. See Federal Trade Commission
filing and review of submitted Funding. See Resources for the drug safety
marketing applications, PDUFA system; User-fee funding system
goal for, 43
history of drug regulation by, 152–153
history of DTC advertising regulation G
by, 160–161
Galson, CDER Director Steven, 207
improving communication with the
GAO. See Government Accountability
public, 187–190
Office
increasingly dependent on industry
Gates Foundation, 212
funding, 71
“General applicability” matters, 134n
interface with industry, 70–75
General Practice Research Database
need for greater accountability and
(GPRD), 112, 200
transparency by, 4
Generic drugs, 159
need for increased resources, 151, 193
Goals. See Performance goals
oversight and review of clinical trial
Government Accountability Office (GAO),
protocols during development,
36, 57, 66, 71–72, 92, 158, 163
PDUFA goal for, ix, 42
Government agencies
public confidence in eroded, 15
compared with private-sector
“regulatory capture” of, 73–74, 155,
counterparts, 68–69
196–197
roles of, 180–181
regulatory decision-making by, ix
GPRD. See General Practice Research
relevant changes at, 210
Database
reports from, 20, 209

INDEX 325
GRMP. See Guidance for Review Staff I

and Industry: Good Review
Management Principles and ICH. See International Conference on
Practices for PDUFA Products Harmonisation
Guidance documents, 208–209 IND. See Investigational New Drug
compared to MAPPs, 77n submission and review process
writing, 41 Indications, re-examination for new, 167
Guidance for Industry: Consumer-Directed The industry. See Pharmaceutical industry
Broadcast Advertisements, 161 Infliximab, 109
Guidance for Industry: Development and Information technology (IT). See also
Use of Risk Minimization Action Databases; Medication information;
Plans, 119, 208 Reference information
Guidance for Industry: Good needs within the CDER, 202
Pharmacovigilance Practices Ingenix Inc., 111–112
and Pharmacoepidemiologic Initial filing review, 40–41
Assessment, 208 in NDAs, 40–41
Guidance for Industry: Investigators, Innovation or Stagnation?—Challenge and
and Reviewers Exploratory IND Opportunity on the Critical Path to
Studies, 208 New Medical Products, 212
Guidance for Industry: Premarketing Risk Instability at the top, and CDER’s
Assessment, 208 organizational dysfunction, 88–90
Guidance for Review Staff and Industry: Institute of Medicine (IOM), ix–x, 2–3, 21,
Good Review Management 24, 50, 66–67, 178, 182
Principles and Practices for PDUFA Committee on Identifying and
Products (GRMP), 78 Preventing Medication Errors, 24
Guidance on Conflict of Interest for workshops, 143
Advisory Committee Members, Institutional review boards (IRBs), 33
Consultants and Experts, 134 Integrated Promotional Services, 56
Intellectual bias, 141
Interdisciplinary tension, 76
H International Conference on Harmonisation
(ICH), 54, 145, 208
Health, commodification of, 184n International Society of
Health care delivery system, 2, 5, 28, 69, Pharmacoepidemiology (ISPE), 112,
177 128
Health care entities, 4–5 Interoffice polarization, and CDER’s
Healthcare databases, automated, 7, organizational dysfunction, 83–85
114–115 Investigational New Drug (IND) submission
Henney, FDA Commissioner Jane, 16, 89 and review process, 25–26, 33–39
Hinchey Amendment, 45 completion of clinical trials and their
History of the Food and Drug limitations, 37–39
Administration (FDA) early clinical trials and related studies,
CDER funding, 194 34–35
CDER staffing, 195 “end of phase 2 meeting” and phase 3
drug regulation by, 152–153 trials, 35–36
DTC advertising regulation, 160–161 pre-new drug application submission
milestones in, 22–23 meeting, 33, 39
HIV/AIDS crisis, 22. See also AIDS roles of the OND and the ODS/OSE
treatment advocacy movement premarket, 36–37
HMO Research Network, 111–112 IOM. See Institute of Medicine
Human subjects, protecting, 33–34 iPLEDGE, 121, 167–168
Hypothesis-testing studies, 143 IRBs. See Institutional review boards

Isotretinoin, 50, 120, 167–168 Manual of Administrative Policies and

ISPE. See International Society of Procedures (MAPPs), 47n, 77, 95
Pharmacoepidemiology Mechanisms of action. See also New
IT. See Information technology molecular entities
of drugs, 2
MedDRA. See Medical Dictionary for
K Regulatory Activities
MedGuides, 50, 157, 186
Kaiser Foundation Research Institute, Medical Dictionary for Regulatory
111–112 Activities (MedDRA), 54, 57
Medical Officer Retention Subcommittee,
82
L Medical records, move toward electronic,
Labeling, 49–51, 167–168. See also Off- 117
label use; Symbol needed to denote Medicare Modernization Act, 113
limited knowledge about new drugs Medicare Part D, 19, 113
changes, 167 Medication guide, 157. See also MedGuides
FDA authority to unilaterally impose Medication information, private-sector
changes, 157–158 developers of, 186
negotiations, 50 Medicine Plus program, 181
recommendations concerning, 11–12, Medicines and Health products Regulatory
169–172 Agency (MHRA), 170
relevant changes at the FDA and MedWatch reporting system, 53–54,
CDER, 210 109–110, 184
Leadership MHRA. See Medicines and Health products
changes at the CDER, 206–207 Regulatory Agency
changes at the FDA, 207–208 Murglitazar, 107
in solving CDER’s organizational
dysfunction, 91–94
Letters N
“Dear Health Practitioner,” 58, 158 NAS. See National Academy of Sciences
sent to drug sponsors in NDAs, 51 Natalizumab, 168
Lifecycle approach National Academies Public Access Records
to drug safety, conditions and Office, 26n
restrictions on distribution National Academy of Sciences (NAS), 92
throughout, 96, 167–170 National Aeronautics and Space
to drugs, 26, 126 Administration, organizational
to risk and benefit, 28, 96 problems at, 67, 82
“Lifestyle” drugs, 21 National Cancer Institute (NCI), 190
Lotronex, 59 National Disease and Therapeutic Index, 56
National Electronic Injury Surveillance
System–Cooperative Drug Adverse
M Event Surveillance System (NEISS–
Management Advisory Board, appointing CADES), 114
an external, 6, 93–94 National Health Service, 171
Management issues in CDER’s National Institute for Health and Clinical
organizational dysfunction, 79–90 Excellence (UK), 125
performance goals for the PDUFA IV, National Institute of General Medical
100 Sciences, 128
solving, 90–91 National Institutes of Health (NIH), 20–21,
Management studies, 68, 89–90, 95 55, 81, 92, 116, 118, 180, 190

INDEX 327
National Library of Medicine (NLM), 143, O

145, 180–181, 183
National Prescription Audit, 56 ODS/OSE. See Office of Drug Safety/Office
National Science Foundation (NSF), 92 of Surveillance and Epidemiology
Natural history of a drug, 31–64 Off-label use, 122
economic impact of drugs, 32 Office of Drug Safety/Office of Surveillance
IND submission and review, 33–39 and Epidemiology (ODS/OSE), 32,
new drug applications, 39–51 48–57, 67, 75–78, 83–86, 129,
postmarket period, 51–59 146, 207
NCI. See National Cancer Institute role in IND submission and review,
NDAs. See New Drug Applications 36–39
Needs, of providers and patients, 178–184 staffing, 107
Negotiations, about label wording, 50 Office of Drug Safety Policy and
NEISS–CADES. See National Electronic Communication. See Office of
Injury Surveillance System– Safety Policy and Communication
Cooperative Drug Adverse Event Office of Generic Drugs, 32
Surveillance System Office of the Inspector General (OIG), 71,
New Drug Applications (NDAs), 22–23, 32, 156
39–51, 106. See also Abbreviated Office of Management and Budget, 18, 95
NDAs; Supplemental NDAs Office of New Drug Chemistry, 78
advisory committees, 44–46 Office of New Drugs (OND), 32–36, 51,
assembly of review team and beginning 56–57, 67, 75–79, 82–86, 105,
of review, 41, 43–44, 77, 96 146, 194–195, 206–207
composition of review teams, 78, 83 role in IND submission and review,
dispute resolution, 47–48 36–37
initial filing review, 40–41 Office of Safety Policy and Communication,
key review meetings, 48 13, 185, 187, 189, 207
letters sent to sponsors, 51, 79 OIG. See Office of the Inspector General
PDUFA timetables and performance OND. See Office of New Drugs
goals triggered, 40 Opinion differences and CDER’s
postapproval requirements and organizational dysfunction, 85–87
labeling, 49–51 Organizational dysfunction in the CDER
review teams, 6, 41, 43–44, 77, 96 culture, 4, 65–100. See also
RiskMAPs, 48–49 Solutions proposed for CDER’s
safety tracking, 46–47 organizational dysfunction
site inspections, 51 inconsistency, 87–88
New drugs, 2, 38, 107–119, 165 instability and politicization, 88–90
New molecular entities (NMEs), 41–44, 98, internal disagreements about handling
106, 166 of safety issues, 47
numbers of priority and standard interoffice polarization, 83–85
approvals, 42 management issues, 79–81
priority reviews of, 41, 133 mass media coverage of, 66, 84
recommendations concerning, 9, 12, policies, and procedures in solving,
133–134, 173 77–90
New vision of drug safety, 26–28 recommendations concerning, 5–7
NIH. See National Institutes of Health scientific disagreement and differences
NLM. See National Library of Medicine of opinion, 85–87
NMEs. See New molecular entities structural factors, 75–77
NSF. See National Science Foundation suboptimal work environment, 81–83
Orphan Drug Act, 152
Over-the-counter (OTC) drugs, 90, 153

P phase 4–postmarketing surveillance,

including further formal
Package inserts, for patients, 185 therapeutic trials, 35, 55, 106, 111,
Patient Health Advisories, 206 117, 133, 157, 211
Patient package inserts, 185 Plan B (emergency contraceptive), 89–91
Patients, 2, 5 Planning advisory committee meetings,
access to drugs, 16 timeline for, 45
advocacy movements for, 177 Polarization, interoffice, 66, 68, 80–85
more engaged and knowledgeable, 21 Policies and procedures, and CDER’s
need to reassure, 147 organizational dysfunction, 77–79
roles and needs of, 178–184 Political considerations, in decision-making,
PDUFA. See Prescription Drug User Fee Act 90–91
Pediatric drugs, 165 Politicization, and CDER’s organizational
Peer-review, 118 dysfunction, 88–90
recommendations concerning, 12, 173 Postmarketing safety of a drug, 51–59, 95–97
Performance goals (suggested for) PDUFA decision-making concerning, ix, 47
IV, 98–100 drug promotion and information,
in performance report to Congress, 52–53
98–100 identifying and evaluating spontaneous
safety-related, 98–100 safety signals, 56–58
Pharmaceutical advertising. See also Direct- need to monitor, 59, 74, 156
to-consumer advertising postmarket data, 55–56
tax deductibility of, 199 recommendations concerning, 8,
Pharmaceutical drugs. See Drugs 127–131
Pharmaceutical industry, 2, 146, 177. See regulatory actions, 58–59
also Sponsors of drugs; User-fee requirements and labeling, in NDAs,
funding system 25, 49–51
communications with the public and risk communication activities and risk
patients, 158, 184, 186 management for the PDUFA IV, 99
credibility of, 4–5, 70 spontaneous adverse event reporting
social responsibility of, 119 system, 53–55
Pharmaceutical Research and Postmarketing study commitments, 155,
Manufacturers of America 172–173, 211
(PhRMA), 89, 123, 143, 162–163, for the PDUFA IV, 99
196 Postmarketing surveillance, including
guiding principles on DTC advertising, further formal therapeutic trials
164 (phase 4), 35
Pharmacoepidemiology PPP. See Pregnancy Prevention Program;
need for career-development awards Public-private partnership
in, 128 Pre-new drug application submission
recommendations concerning, 9, meeting, 39
134–141 Preapproval period, 37, 123, 154–155
Pharmacogenomics, 34 safety conferences during, 48
Pharmacovigilance, 208 Predictive Safety Testing Consortium, 213
Phases of clinical trials and medicine Pregnancy Prevention Program (PPP), 120
development, 35 Premarket clinical trials, 38
phase 1–clinical pharmacology studies, Prescribers’ understanding, 5
34–35, 37 Prescription Drug User Fee Act (PDUFA),
phase 2–clinical investigation studies, 15, 66, 70–74, 116, 154–155, 193.
34–35, 37 See also User-fee funding system
phase 3–formal clinical trials, 35–36, clinical development of, 42
124 deadlines in, 49

INDEX 329
FDA filing and review of submitted The public, 2, 5, 28

marketing applications, 43 improving communication with,
FDA oversight and review of clinical 187–190
trial protocols during development, perspectives on DTC advertising, 162
42 Public Employees for Environmental
goals of, 42–43 Responsibility, 86n
in NDAs, 40 Public Health Advisories, 206
PDUFA I, 16, 23, 72 Public-private partnership (PPP), 8, 117–
PDUFA II, 16, 23, 35–36, 40, 72–73 119, 201
PDUFA III, 35–36, 40, 48–49, 73, 121 Pure Food and Drug Act, ix, 19n, 22, 152,
PDUFA IV, 98–100 184
Reauthorization Performance Goals
and Procedures, 23
short history of, 72–73 Q
sponsor-requested meetings with FDA
Quality-adjusted life years (QALYs), 125
during clinical development, 42–43
sunset of approaching, 19
timetables and performance goals
triggered, 40 R
Prescription Drug User Fee Act (PDUFA): Randomized controlled trials, 86
Adding Resources and Improving Rationale for strengthening drug regulation,
Performance in FDA Review of 164–166
New Drug Applications, 209 realistic regulatory action on safety
Prescription drugs needed, without the “last call” of
off-label use, 122 approvals, 166
providers’ knowledge about, 179 Reauthorization Performance Goals and
safety of, 1–2 Procedures (PDUFA), 23, 196–199
taking multiple, 153 Recent FDA materials, 208–209
Prescriptions, taxing, 198 guidance documents, 41, 208–209
Preventing Medication Errors, 50, 178, 182 reports, 209
recommendations from, 180–183 Recommendations, 5–14
Princeton Survey Research Associates, 162 adverse event reporting, 7, 114–115
Priority reviews, 133 advisory committees, 9–10, 12,
of new molecular entities, 41 133–142, 188–189
Product seizures, 58 AERS, 7, 110
Product submissions, reductions in, 133 amending the FD&C Act, 5–6, 92–93
Professional opinions. See Differing automated healthcare databases, 7,
professional opinion procedure 114–115
Professional societies, 4–5 better science and expertise, 7–10
Program reviews or evaluations, 211–212 CDER review teams, 10, 146–147
advisory committees, 211 clinical trials, 10, 144–145
partnerships, 211–212 for the Commissioner of the FDA, 5–6,
postmarketing study commitments, 9, 92–93, 131
211 communication about safety, 12–13,
Project managers, 34 188–189
Promotion of drugs to patients. See also conflicts of interest, 10, 141–142
Direct-to-consumer advertising; for Congress, 6–8, 11–13, 98–100,
Pharmaceutical advertising 117–119, 169–172, 197–203
increases in, 21 for consumers, 180–181
Propulsid, 17 direct-to-consumer advertising, 11–12,
Protection of human subjects, 33 169–172
Providers, roles and needs of, 178–184

external Management Advisory Board, Resources for the drug safety system, 5,
6, 93–94 166, 193–204
FDA authority, 11, 170 levels required to enable CDER to
labeling, 11, 169–170 support the FDA mission, 4
NDA, 10, 144–146 recommendations concerning, 13–14,
NDA review teams, 6, 96 197–203
new molecular entities, 9, 12, 133– Review elements for new drug approval
134, 173 beginning in NDAs, 41, 43–44
Office of Drug Safety Policy and current, 52
Communication, 13, 189 data on NMEs, 172–173
organizational culture, 5–7 meetings key in NDAs, 48
peer-review, 12, 173 Review Panel on New Drug Regulation, 74,
pharmacoepidemiology, 9, 134–141 155–156, 172
postmarketing safety of a drug, 8, Review teams, 34
127–131 composition of, 78, 83
from Preventing Medication Errors, in NDAs, assembling, 41, 43–44
180–183 Risk-benefit analyses
for providers and patients, 182–183 for approval decisions, 106–107, 166
public-private partnership, 8, 117–119 evolving throughout the drug’s
regulation, 10–12 lifecycle, 2, 4, 96, 121–126
resources, 13–14, 197–203 recommendations concerning, 8,
risk-benefit analyses, 8, 125–126 125–126
risk management, 11, 169–170 Risk communication activities, 27
RiskMAPs, 8, 121 postmarket, 97
safety-related performance goals for Risk management
the PDUFA IV, 6–7, 98–100 postmarket, 97
for the Secretary of DHHS, 6, 8, recommendations concerning, 11,
93–94, 117–119 169–170
Reference information, access to Risk Minimization Action Plans
comprehensive, 182 (RiskMAPs), 119–121, 146, 167
Regulatory activities for safety, 4, 31. See developing and assessing, 57, 158
also Enforcement tools in NDAs, 48–49
in the postmarket period, 58–59 Rofecoxib, 17, 55, 168
realistic needed, without the “last call” Roles, of providers and patients (in drug
of approvals, 166 safety system), 5, 178–184
recommendations concerning, 10–12 Rolling reviews, 39–40
Regulatory authority necessary to provide
for drug safety, 4, 27, 151–176. See
also Food and Drug Administration S
authority
Safety data, gaps in, 37
an aging and inadequate statutory
Safety officers, 37
framework, 153–166
Safety-related performance goals for the
history of FDA drug regulation,
PDUFA IV, 98–100
152–153
expertise in preapproval evaluation, 98
strengthening FDA’s regulatory
monitoring of adverse drug reactions
authority, 167–173
and the AERS, 98
“Regulatory briefings,” 46
performance management, 100
“Regulatory capture” of the FDA, 73–74,
postmarketing risk communication
155, 196–197
activities and risk management, 99
Regulatory “tool kit,” 168, 213
postmarketing study commitments, 99
Research. See Academic research enterprise

INDEX 331
Safety signals, 27, 84. See also Spontaneous Special symbol needed to denote limited
safety signals in the postmarket knowledge about new drugs,
period 170–172. See also Black triangle
in generation, 108–110 Sponsors of drugs
reducing uncertainty about and benefit letters sent to, 51
after approval, 108–115 materials generated by, 52
in strengthening and testing, 110–115 meeting with FDA during clinical
Safety teams, of epidemiologists, 88 development, PDUFA goal for,
Safety “tool kits,” 213 42–43
Safety tracking, 46–47 non-compliance by, 18
in NDAs, 46–47 obligations of, 34
Science-based decision-making, 66, 129 Spontaneous safety signals in the
Science of safety, 27, 105–150 postmarket period
benefits after approval, 107–119, 122 AERS, 53–55
credibility of, 126–147 identifying and evaluating, 56–58
generating, 106–126 Stakeholders, 2, 4, 177. See also individual
and recommendations concerning stakeholders
expertise, 7–10 Statement of task. See The charge (to the
reducing uncertainty about, 107–119, committee)
122 Statutory framework (for drug regulation)
rigor in, 27 aging of, 153–166
risk-benefit analyses throughout the FDA authority after approval, 155–164
drug’s lifecycle, 121–126 FDA authority preapproval, 154–155
risk minimization action plans, inadequacy of, 153–166
119–121 rationale for strengthening, 164–166
understanding risk and benefit for Steering Committee for the Collaborative
approval decisions, 66, 106–107 Development of a Long-Range
Scientific advances, 28. See also Academic Action Plan for the Provision
research enterprise of Useful Prescription Medicine
increasing the numbers of targeted Information, 186
drugs, 20 Strengthening FDA’s regulatory authority,
Scientific disagreement, and CDER’s 167–173
organizational dysfunction, 85–87 conditions and restrictions on
Scientific reviewers, 34 distribution throughout the drug
Secretary of Health and Human Services, 6, lifecycle, 167–170
45, 93–94, 97 greater regulatory flexibility post
Sector maps, 110 approval, 166
Signals. See Safety signals periodic review of data on NMEs,
Site inspections, 51 172–173
in NDAs, 51 special symbol needed to denote
SMART (System to Manage Accutane limited knowledge about new
Related Teratogenicity), 120–121 drugs, 170–172
Social Security Administration, 92 Structural changes in the CDER, 206–207
Solutions proposed for CDER’s Structural factors in CDER’s organizational
organizational dysfunction, dysfunction, 75–77
90–100 solving, 94–97
agency leadership, 91–94 Study process, 25–26
external environment, 97–100 Supplemental NDAs, 31
management, 90–91 Supplements, dietary, 153
structural factors, 94–97 Surrogate endpoints, 107
“Special Government Employees,” 131, 211 Suspension of approval, 173

T V
Taxing prescriptions, 198 VA. See Department of Veterans Affairs
“Team approach,” 76. See also Review Vaccine Safety Datalink (VSD), 112
teams; Safety teams Valdecoxib, 17
Terfenadine, 109 Vanderbilt University, 111
Terminology coding, 54 Veterans Health Administration, 92
Thompson v. Western States Medical Vioxx, 65
Center, 160 Virginia State Board of Pharmacy v.
Throckmorton, CDER Deputy Director Virginia Citizens Consumer
Douglas, 207 Council, Inc., 159
Timeline, for planning advisory committee Vision. See New vision of drug safety
meetings, 45 von Eschenbach, FDA Acting Commissioner
Toxicologic studies, 44 Andrew, 86n
Transparency VSD. See Vaccine Safety Datalink
and the credibility of safety science,
142–147
need for greater, 4–5, 124, 127 W
Troglitazone, 17, 50, 109
Wall Street Journal, 162
Tufts Center for the Study of Drug
Warning the public about drug safety risks,
Development, 71
1. See also Black box warnings;
Labeling
Washington Legal Foundation, 162
U
Web sites, 25, 140, 142–143, 159, 172,
Uncertainty, disagreement in the face of, 179, 181, 187, 190, 210
127 WHI. See Women’s Health Initiative
Under-reporting of adverse events, WHO. See World Health Organization
substantial, 55, 109 Withdrawals, 1–2, 16, 165, 173
Union of Concerned Scientists, 86n Women’s Health Initiative (WHI), 55, 115,
University of Arizona, 213 123–124, 181
US drug safety system. See also Committee World Health Organization (WHO), 143,
on the Assessment of the US Drug 145, 212
Safety System
impaired by, 4
an improved, 13–14 Z
a transformed, 4
Zero-tolerance policy, regarding COI
Useful consumer medication information,
considerations, 140–141
criteria for, 187
User-fee funding system, 16, 23, 40, 70, 83,
196–197

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THE NATIONAL ACADEMIES PRESS

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The Future of Drug Safety: Promoting and Protecting the

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Committee on the Assessment of the US Drug Safety System

Board on Population Health and Public Health Practice

Alina Baciu, Kathleen Stratton, Sheila P. Burke, Editors

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Library of Congress Cataloging-in-Publication Data

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Printed in the United States of America.

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“Knowing is not enough; we must apply.

Advising the Nation. Improving Health.

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The Institute of Medicine was established in 1970 by the National Academy of

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COMMITTEE ON THE ASSESSMENT

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Board on Population Health and Public Health Practice Board Liaison

GEORGE ISHAM, M.D., M.S., Medical Director and Chief Health

KATHLEEN STRATTON, Ph.D., Study Director

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J. Lyle Bootman, College of Pharmacy–Pulido Center, The University

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Anne Khademian, Center for Public Administration and Policy,

Although the reviewers listed above have provided many constructive

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Research (CDER), combined with severe resource constraints and a prob-

Sheila P. Burke, Chair

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2 NATURAL HISTORY OF A DRUG 31

4 THE SCIENCE OF SAFETY 105

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Credibility of the Science, 126

5 REGULATORY AUTHORITIES FOR DRUG SAFETY 151

6 COMMUNICATING ABOUT SAFETY 177

7 RESOURCES FOR THE DRUG SAFETY SYSTEM 193

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 THE FUTURE OF DRUG SAFETY

perceived rush to approve drugs without sufficient attention to safety, and

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 THE FUTURE OF DRUG SAFETY

• The organizational culture of CDER and its determinants, and how

In its information gathering, the committee became aware of multiple

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Instability in the Office of the Commissioner has been a serious problem

3.1: The committee recommends that the FD&C Act be amended

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 THE FUTURE OF DRUG SAFETY

pointed for a 6-year term of office. The Commissioner should be

A mechanism is needed to allow the agency and CDER leadership to

THE FUTURE OF DRUG SAFETY

THE FUTURE OF DRUG SAFETY

THE FUTURE OF DRUG SAFETY

THE FUTURE OF DRUG SAFETY

in five major areas: organizational culture and leadership, science, regulatory